TW201216961A - Estrogen receptor modulators and uses thereof - Google Patents

Abstract

Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

Description

201216961 VI. Description of the Invention: [Technical Field of the Invention] The compounds (including pharmaceutically acceptable salts, solvates, metabolites, prodrugs thereof), methods of preparing the same, and pharmaceuticals comprising the same are described herein. Compositions, and methods of using the same to treat, prevent or diagnose estrogen sensitivity, estrogen receptor dependent or estrogen receptor mediated diseases or conditions. The present application claims the following documents: The title of the US Provisional Patent Application No. 61/383,659, entitled "ESTROGEN RECEPTOR MODULATORS AND USES THEREOF", filed on September 16, 2010, and the title of the application filed on November 5, 2010 U.S. Provisional Patent Application No. 61/410,727, entitled "ESTROGEN RECEPTOR MODULATORS AND USES THEREOF", US Provisional Patent Application No. 61/410,727, issued February 25, 2011, to ESTROGEN RECEPTOR MODULATORS AND USES THEREOF No. 10 0 428 8.4, filed on March 15, 2011, the content of which is hereby incorporated by reference. [Prior Art] An estrogen receptor ("ER") is a ligand-activated transcriptional regulatory protein that mediates the interaction of various biological effects through its interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. ER has been found to have two isoforms, ER-α and ER-β. Estrogen and estrogen receptors and many diseases 158421.doc 201216961 or pathological conditions, such as breast cancer, that is, nest cancer, cancer, prostate cancer, endometrial cancer, uterine cancer, and other diseases or conditions. SUMMARY OF THE INVENTION In the present invention, a compound of the formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide, which reduces the effects of estrogen and estrogen receptors and/or reduces estrogen incineration Concentration, and thus as a medicament for the treatment or prevention of diseases or conditions in which the action of estrogen and/or estrogen receptors is involved in the disease or (4) the etiology or (4) learning or causing the disease or condition At least one symptom and wherein such effects of estrogen and/or estrogen receptor are undesirable. In some embodiments, the compounds disclosed herein are estrogen receptor degrading agent compounds. In one aspect, the compound of formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide, is used to treat a related disease or condition, and (4) the disease, disease or condition includes, but is not limited to, cancer (eg, EM dysfunction associated with bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, and uterine cancer, leiomyomas (eg, uterine leiomyoma), and middle sacral nervous system (CNS) defects (eg Alcoholism, migraine), defects in the d-tube system (eg aortic aneurysm, susceptibility to myocardial infarction, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension), hematological system defects (eg deep veins Immune and inflammatory diseases (such as Graves' Disease, arthritis, multiple sclerosis, cirrhosis), infection sensitivity (such as hepatitis B, chronic liver disease), metabolic defects (such as bone density, cholestasis) , hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis), neurological deficits (eg Alzheimer's disease (Alzheimer, s 158421.doc 201216961 disease), Parkinson's disease (parkinso) n, s disease), psychiatric defects (such as anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depression, psychosis) and reproductive defects (such as age at onset, intrauterine Membrane ectopic disease, infertility in one aspect - The compound of formula (I), its pharmaceutically acceptable salts, solvates, N-oxides, metabolites and prodrugs are described herein. The compound of formula (1) is estrogen Receptor Modulators. In some embodiments, the compound of Formula (1) is an estrogen receptor antagonist. In some embodiments, the compound of Formula (1) is an estrogen receptor degrading agent. In some embodiments, the compound of Formula (I) An estrogen receptor antagonist and an estrogen receptor degrading agent. In some embodiments, the compound of the formula exhibits minimal or no estrogen receptor agonist activity. In some embodiments, in therapy In the context of cancer, the compound of formula (1) provides improved therapeutic activity characterized by complete or prolonged tumor regression, lower incidence or rate of therapeutic resistance, and/or tumor aggressiveness. Small In one aspect, provided herein is a compound of formula ⑴ acceptable, or a pharmaceutically acceptable salt or N- oxide:

Formula (1), wherein Z-type - 0H or -OR10; R-based CVC4 ray, CVC4 gas-burning group, C--C4 atmosphere, c3-C6 ring 158421.doc 201216961 alkyl, or -CVC4 alkyl- W; W is a hydroxyl group, a halogen, a CN, a cvc4 alkyl group, a Cl-C4 haloalkyl group, a CVC4 alkoxy group, a CVCU haloalkoxy group, or a c3_c6 cycloalkyl group; each R3 is independently a halogen, a C1-C4 alkyl group. Or c丨-c4 fluoroalkyl; each R4 is independently halogen, -CN, -OR9, -s(=〇)2r10, Ci-C4 alkyl, CVC4 fluoroalkyl, or 0^-(:4 Alkyl; each R independently of a cyclin, -CN, -OR9, _s(〇)2r10, C1-C4 phenotype, CrCelt alkyl, or C"C4 heteroalkyl; R6 Η, CVC4 alkyl, or A dentine; R7 is H, a Ci_c4 alkyl group, or a halogen; R is a hydrazine, a CVC6 alkyl group, a CVCs fluoroalkyl group, or an alkyl group;

Rl() is CVC6 alkyl; m is 0, 1, or 2, n is 〇, 1, 2, 3, or 4; and p is 〇, 1, or 2 〇 In some embodiments, a compound of formula (1), Or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable n, or Ν-oxide having the structure of formula (π), or a pharmaceutically acceptable salt thereof, or a cerium oxide. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable compound thereof, as set forth in Table 1, or a pharmaceutically acceptable salt thereof. Throughout the specification t', the group can be selected and the base can be selected to provide a stable moiety and compound. The compounds disclosed herein are estrogen receptor modulators. In some embodiments, the compounds disclosed herein have high specificity for the estrogen receptor and have desirable, selective pharmacological activities. Desired Tissue Selective Pharmacology J58421.doc -6 - 201216961 Activity includes, but is not limited to, £11 antagonist activity in breast cells and minimal ER agonist activity in uterocytes or no ER agonist activity. In some embodiments, the compounds disclosed herein are estrogen receptor degrading agents which exhibit complete estrogen receptor antagonist activity and have negligible or minimal estrogen receptor agonist activity. In some embodiments, the compounds disclosed herein are estrogen receptor degrading agents. In some embodiments, the compounds disclosed herein are estrogen receptor antagonists. In some embodiments, the compounds disclosed herein have minimal or negligible estrogen receptor agonist activity. In some embodiments, presented herein are compounds selected from the group consisting of active metabolites, tautomers, pharmaceutically acceptable solvates, pharmaceutically acceptable salts or prodrugs of the compounds of formula (1). Also described are pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide. In some embodiments, the pharmaceutical compositions also contain at least one pharmaceutically acceptable inert ingredient. In some embodiments, the pharmaceutical compositions are formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration. In some embodiments, the pharmaceutical composition is a troche, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a suspension, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition further comprises one or more other therapeutically active agents selected from the group consisting of corticosteroids, antiemetics, analgesics, anticancer drugs, anti-inflammatory drugs, kinase inhibitors, antibodies, HSP90 inhibitors. , histone deacetylase (HDAC) inhibitor, poly ADP-ribose polymerase (PARP) inhibitor, and aromatase inhibitor. 158421.doc 201216961 In some embodiments, provided herein is a method comprising administering a compound of formula (1) to a human having an estrogen sensitive, estrogen receptor mediated or estrogen receptor dependent disease or condition Or a pharmaceutically acceptable salt thereof, or an N-oxide. In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide, has been administered to humans - or a plurality of other therapeutically active agents. In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a oxy-compound. In some embodiments, in addition to a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an N-oxide, one or more additional therapeutically active agents are selected from the group consisting of: corticosteroids, antiemetics, analgesics, antibiotics Cancer agents, anti-inflammatory drugs, kinase inhibitors, antibodies, HSP90 inhibitors, histone deacetylase (HDAC) inhibitors, and aromatase inhibitors. In some embodiments, the methods further comprise administering radiation therapy to the mammal. In certain embodiments, the compounds of the methods are administered before or after surgery. In certain embodiments, the methods comprise administering to the mammal at least one other anticancer agent. In some embodiments, a method of treating cancer in a mammal is provided, comprising administering to the mammal a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide. In certain embodiments, the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer, or lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is a hormone dependent cancer. In certain embodiments, the cancer is an estrogen receptor dependent cancer. In certain embodiments, the cancer is estrogen sensitive 158421.doc 201216961 inductive cancer. In certain embodiments, 'cancer resistance is anti-hormone therapy. In certain embodiments, the cancer is an estrogen sensitive cancer or an estrogen receptor dependent cancer that is resistant to anti-hormone therapy. In some embodiments, the anti-hormone therapy comprises treatment with at least one agent selected from the group consisting of tamoxifen, fulvestrant, steroid aromatase inhibitors, and non-steroidal aromatase inhibitors. In some embodiments, the methods further comprise administering radiation therapy to the mammal. In certain embodiments, the compounds of the methods are administered before or after surgery. In some embodiments, the methods comprise administering to the mammal at least one other anticancer agent. In some embodiments, a method of treating a hormone receptor positive metastatic breast cancer in a postmenopausal female having disease progression after antiestrogen therapy, comprising administering to the woman an estrogen receptor degrading compound of formula (1), or Its medicine can accept the salt of the party, or N-oxide. In some embodiments, the methods further comprise administering radiation therapy to the mammal. In certain embodiments, the compounds of the methods are administered before or after surgery. In certain embodiments, the methods comprise administering to the mammal at least one other diterpene treatment of the breast or genital tract of the mammal: a method of treating a benign or malignant disease, including to the mammal A compound of formula (1), a pharmaceutically acceptable salt thereof, or oxidized/in some embodiments, a benign or malignant disease is a breast cancer. In some embodiments, the methods further include administering radiation therapy to the mammal. In some embodiments, 158421. (j〇, 201216961 compounds) is administered at or after the surgical squamous surgery. In some embodiments, the methods include administering to a mammal. At least one other anticancer agent. In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an N·oxide is used to treat postmenopausal women who have disease progression after antiestrogen therapy Hormone receptor-positive metastatic breast cancer. In some embodiments, the use of a compound to treat a hormone-dependent benign or malignant disease of the breast or genital tract in a mammal also provides a method of reducing ER activation in a mammal, including The mammal is administered a compound having at least one structure of formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide. In some embodiments, the method comprises reducing breast cells, ovarian cells, ER activation in colon cells, prostate cells, endometrial cells, or uterine cells. In some embodiments, methods of reducing ER activation in a mammal include reducing lactation The combination of estrogen and estrogen receptor m, a method of reducing ER activation in a mammal comprising reducing a compound of formula (I) in a mammal, or a pharmaceutically acceptable compound thereof Use of a salt or ice oxide in the manufacture of a medicament for the treatment of estrogen sensitivity, estrogen receptor dependent or estrogen receptor mediated disease or condition. In some embodiments The disease or condition is breast cancer, Indian cancer, colon cancer, prostate cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is the following disease or condition in a mammal: bone cancer , breast cancer, colorectal cancer, intrauterine cancer, prostate cancer, (four) cancer, uterine cancer, cervical cancer, lung cancer, alcoholism, migraine, aortic aneurysm, 158421.doc •10· 201216961 myocardial infarction susceptibility, main Arteriosclerosis, cardiovascular disease, coronary artery disease, southern blood pressure, deep vein thrombosis, Graves' disease, arthritis, multiple sclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density, cholestasis, hypospadias ,fat Symptoms, osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease, Parkinson's disease, migraine, dizziness, anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depression, Psychosis, age at menstruation, endometriosis, or infertility. In some embodiments, the disease or condition is set forth herein. In some instances, the compounds of formula (I), or their medicinal properties, are disclosed herein. The use of an extractable salt, or N-oxide, for the treatment or prevention of estrogen sensitivity, estrogen receptor dependent or estrogen receptor mediated diseases or conditions. In some embodiments, the disease Or the condition is set forth herein. In any of the embodiments disclosed herein, the mammal is a human. In some embodiments, 'the compounds provided herein are used to reduce, alleviate, or eliminate estrogen receptors. active. Other objects, features, and advantages of the compounds, methods, and compositions described herein will be apparent from the Detailed Description. It should be understood, however, that the description, and claims, and,,,, Various changes and modifications. [Embodiment] Estrogen receptor a (ER-a; NR3A1) and estrogen receptor β (ΕΙι_β; NR3A2) are steroid-like receptors, which are members of the large nuclear receptor superfamily. Nuclear receptors share a common modular structure comprising at least 158421.doc -11 - 201216961 DNA binding domain (DBD) and ligand binding domain (LBD). The steroid hormone is used by the system as a soluble intracellular protein that regulates the transcription factor of the ligand. Vertebrates contain five closely related steroid hormone receptors (estrogen receptor, androgen receptor, progesterone receptor, glucocorticoid receptor, mineralocorticoid receptor), which regulate various regeneration and metabolism. And developmental activity. The activity of ER is controlled by binding endogenous estrogens (including 17?-estradiol and females). The ER-α gene is located on 6q25.1 and encodes the 595 ΑΑ protein. The ER-β gene is located on chromosome 14q23.3 and produces a 530 AA protein. However, each of these genes can produce multiple isoforms due to alternate splicing and translation initiation sites. In addition to the DN A binding domain (referred to as the c domain) and the ligand binding domain (E domain), the receptors contain an N-terminal (A/B) domain and a hinge linking the C and E domains. (D) domain, and c_terminal extension (F domain) (Gronemeyer and Laudet; Protein Profile 2: 1173-1308, 1995). Although the ER-α and ER-β (: and £ domains are fairly conserved (95% and 55% amino acid identity, respectively), the A/B, D&F domains are less conserved (lower) At 30% amino acid identity. Both receptors are involved in the regulation and development of the female reproductive tract, and also play different roles in the central nervous system, cardiovascular system and bone metabolism. The bulk binding pocket is deeply embedded in the ligand binding domain. Upon binding, the ligand becomes part of the hydrophobic core of this domain. Therefore, most steroid hormone receptors are unstable in the absence of hormones and require a partner The help of proteins (such as Hsp9〇) to maintain hormone binding ability. The interaction with Hsp90 also controls the nuclear transduction of these receptors. 158421.doc 201216961. Ligand binding stabilizes the receptor and causes the following sequential conformational changes: release partner a protein that alters the interaction between various receptor domains and the surface of the reconstituted protein that translocates the receptors into the nucleus, binds to DNA and participates in the interaction between the chromosomal recombination complex and the transcriptional machinery Although ER can interact with Hsp90, this interaction is not required for hormone binding, and depending on the cellular environment, apo-ER can be cytoplasmic and nuclear. Biophysical studies have shown that DNA binding (rather than matching) Body binding) promotes receptor stability (Greenfield et al, Biochemistry 40: 6646-6652, 2001) ° ER can be directly linked to a specific DNA sequence motif (called an estrogen response element (ERE)) Typical pathways), or indirectly via DNA-protein interactions (atypical pathways) (Welboren et al, Endocrine-Related Cancer 16: 1073-1089, 2009). In atypical pathways, ER has been shown Binding to other transcription factors including SP-1, AP-1 and NF_kB. These interactions appear to play an important role in the ability of ER to regulate cell proliferation and differentiation. Both types of ER DNA interactions can cause gene activation or inhibition. 'Depending on the transcriptional co-regulators raised by the individual ER-ERE complexes (Klinge, Steroid 65: 227-251, 2000). The recruitment of helper modulators is mainly caused by the interaction of two proteins on the surface AF2. And AF1 mediation. AF2 is located in the ER E domain' and its conformation is directly regulated by ligands (Brzozowski et al., Nature 389: 753-758, 1997). Full agonists appear to promote the recruitment of co-activators, while weakly excited Agents and antagonists promote the binding of adjuvant inhibitors. AF1 is less fully understood for protein regulation, but can be controlled by phosphorylation of serine 158421.doc 201216961 (Ward and Weigel, Biofactors 35: 528 536, 2009). One of the related phosphorylation sites (S118) appears to control the transcriptional activity of ER in the presence of an antagonist such as tamoxifen, which plays an important role in the treatment of breast cancer. Although full agonists appear to block ER in certain conformations, weak agonists tend to maintain ER balance between different conformations, leaving cell-dependent differences in the helper modulator profile to modulate E R activity in a cell-dependent manner.

(Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). The interaction of ER with DNA is dynamic and includes, but is not limited to, proteasome degradation of ER (Reid et al, M〇i Cell 11: 695 7〇7, 2〇〇3). Ligands provide an attractive therapeutic strategy for the degradation of ER for use in estrogen-sensitive and/or resistant to diseases or conditions in which anti-hormone therapy is available. ER signaling is critical for the development and maintenance of female reproductive organs (including breasts), ovulation, and thickening of the endometrium. 6-foot signaling also plays a role in bone mass, lipid metabolism, cancer, and the like. About 7% of breast cancers exhibit ER-a (ER-a positive) and depend on estrogen for growth and survival. Other cancers are also thought to be dependent on growth and survival of ER-a signaling, such as ovarian cancer and sub-endothelin. The anti-agent tamoxifen has been used to treat early and late ER a-positive breast cancer in women before and after menopause. Fluvistide (FaSl〇dexTM' steroid-based ER antagonist) is used to treat breast cancer in women who have progressed with tamoxifen. Steroids and non-steroidal aromatase inhibitors are also used to treat cancer in humans. In some embodiments, steroid and non-steroidal aromatase inhibitors block estrogen production in menopausal women from androstenone and testosterone, thereby blocking ER-dependent growth in cancer. In addition to these antihormonal agents, various other chemotherapeutic agents 15842丨.doc 201216961 (e.g., anthracycline, platinum, taxanes) are used to treat progressive ER-positive breast cancer. In some cases, the monoclonal antibody trastuzumab (HerceptinTM) or the small molecule pan-ERB-B inhibitor lapatinib is used to treat ERB-B/HER2 tyrosine kinase. Receptor gene amplification of ER-positive breast cancer. Despite the use of this group of anti-hormone, chemotherapy and small molecule and antibody-based targeted therapies, many women with ER-α positive breasts develop progressive metastatic disease and require new therapies. Importantly, most ER-positive tumors that progress in existing anti-hormone and other therapies are thought to still depend on ER-a for growth and survival. Therefore, there is a need for new ER-a targeting agents that are active in metastatic disease and acquired resistant environments. In one aspect, a selective estrogen receptor modulator (SERM) compound is described herein. In a particular embodiment, the SERM described herein is a selective estrogen receptor degrading agent (SERD). In some embodiments, in cell-based assays, the compounds described herein reduce steady-state ER-a content (ie, ER degradation) and are used to treat estrogen-sensitive diseases or conditions and/or anti-hormones The treatment produces a disease or condition that is resistant. In some embodiments, the compounds disclosed herein minimize the level of estrogen receptors in the nucleus. Given the central role of ER-a in the development and progression of breast cancer, the compounds disclosed herein are used alone or in combination with other agents that modulate other critical pathways in breast cancer for the treatment of breast cancer, including but not limited to their targeting of IGF1R , EGFR, erB-B2 and 3, PI3K/AKT/mTOR axis, HSP90, PARP or histone deacetylase. In view of the central role of ER-a in the development and progression of breast cancer, the compounds disclosed herein are used alone or in combination with other agents for the treatment of breast cancer for the treatment of 158421.doc -15-201216961 breast cancer, including but not limited to aroma Enzyme inhibitor, anthracycline, platinum, nitrogen mustard alkylation reagent, taxane. Exemplary agents for the treatment of breast cancer include, but are not limited to, paclitaxel, anastrozole, exemestane, cyci〇ph〇sphamide, Epibibicin, fulvestrant, letrozole etr〇z〇le), gemcitabine, trastuzumab, pegfilgrastim, filgrastim , tamoxifen, docetaxel, toremifene, vinorelbine, capeeitabine, ixabepilone, and as described herein Other medicines. ER-related diseases or conditions (associated with the agents disclosed herein) include ER-a functions also associated with cancer (bone, breast, colorectal, endometrial, prostate, ovarian, and uterine) Obstruction, leiomyoma (uterine leiomyoma), central nervous system (CNS) deficiency (alcoholism, migraine), cardiovascular system defects (aortic aneurysm, myocardial infarction susceptibility, aortic valve sclerosis, cardiovascular disease, Coronary artery disease, hypertension), hematological system defects (deep vein thrombosis), immune and inflammatory diseases (Graves' disease, arthritis, multiple sclerosis, cirrhosis), infection sensitivity (hepatitis B, chronic liver disease) , metabolic defects (bone density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis), neurological deficits (Alzheimer's disease, Parkinson's disease, migraine, dizziness), Psychiatric defects (neurological anorexia, attention deficit hyperactivity disorder (ADHD), dementia, major depression, psychosis) and reproductive defects (menstrual age, endometriosis) Disease, infertility). 15842l.doc • 16· 201216961 In some embodiments, the compounds disclosed herein are used to treat cancers of mammals. In some embodiments, the cancer is breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, cervical cancer, or lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is a hormone dependent cancer. In some embodiments, the cancer is an estrogen receptor dependent cancer. In some embodiments, the cancer is an estrogen sensitive cancer. In some embodiments, the cancer is resistant to anti-hormone therapy. In some embodiments, the cancer is resistant to an anti-hormone-treated estrogen-sensitive cancer or an estrogen receptor-dependent cancer. In some embodiments, the anti-hormone therapy comprises treatment with at least one agent selected from the group consisting of tamoxifen, fulvestrant, a steroid aromatase inhibitor, and a non-steroidal aromatase inhibitor. In some embodiments, the compounds disclosed herein are used to treat hormone receptor positive metastatic breast cancer in postmenopausal women who have disease progression after antiestrogen therapy. In some embodiments, the compounds disclosed herein are used to treat a hormone-dependent benign or malignant disease of a mammalian/middle breast or a thin atrophy. In some embodiments, the benign or malignant disease is breast cancer. In some embodiments, the compounds disclosed herein are used to treat cancers of mammals wherein the mammal does not receive chemotherapy. Cancers In some embodiments, the compounds disclosed herein are used to treat mammalian cancer, wherein at least one anticancer drug is used to treat the mammal. In the embodiment - the cancer is a hormone refractory cancer. In some embodiments, endometriosis uses the compounds disclosed herein to treat mammals. 158421.doc -17 201216961 In some embodiments, the compounds disclosed herein are used to treat mammalian leiomyomas. In some embodiments, the leiomyomas are uterine leiomyomas, esophageal leiomyomas, cutaneous leiomyomas, or small intestinal leiomyomas. In some embodiments, the compounds disclosed herein are used to treat a fibroma of a mammal (e.g., uterine fibroids). Compounds: The compounds of formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are estrogen receptor modulators. In a specific embodiment, the compounds described herein are estrogen receptor degrading agents. In a particular embodiment, the compounds described herein are estrogen receptor antagonists. In a particular embodiment, the compounds described herein are hormone receptor degrading agents and estrogen receptor antagonists having minimal estrogen receptor agonist activity or no hormone receptor agonist activity. In some embodiments, the compounds disclosed herein are estrogen receptor degrading agents and estrogen receptor antagonists that exhibit minimal or no estrogen and agonism, and/or resistance to breast cancer, nest cancer, and uterus. Antiproliferative activity of endometrial cancer, cervical cancer cell lines; and/or resistance to breast cancer, ovarian cancer, endometrial cancer, maximal antiproliferative efficacy of cervical cell lines, and/or human endometrium (Ishikawa) minimal agonism in cell lines; and/or no agonism in human endometrial (Ishikawa) cell lines; and/or minimal or no agonism in uterine analysis of immature rats in vivo; / or inverse agonism in the analysis of uterus in immature rats in vivo; and / or breast cancer, ovarian cancer, endometrial cancer, cervical cancer cell lines or other cancers in the analysis of in vivo xenografts. Doc • 18 · 201216961 Antitumor activity in rodent models. In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an N-oxide:

Formula (1) wherein Z is -OH or -OR10; alkyl, CVC4 fluoroalkyl, Ci-cu 氘 alkyl, c3_c^ alkyl, or -C!-C4 alkyl-w; w-hydroxyl, halogen, CN, CVC4 alkyl, CVc4 calcining group, C1-C4 ritual base, Ci-Cij dentate oxy group, or 〇3-〇6 ring pit; each R3 is independently halogen, c丨-C4 alkyl, Or C丨-C4 fluoroalkyl; each R4 independently dentate, -CN, -OR9, -S(=0)2R1〇, Ci_c4^, CVC4 fluoroalkyl, or CVC4 heteroalkyl; each R5 independent The system is _ prime, -CN, -OR9, -S(=〇)2Ri. , Ci_c4^ group, alkyl group, or C1-C4 miscible group; R6 system Η, CVC4 alkyl group, or _ 素; 尺 7 system ^ 1, Ci_C4 alkyl, or dentate; R system Η, CVC6 alkyl, (VC6 fluoroalkyl, or alkyl; alkyl; or 4; and p is 〇, 1, or m is 〇, 1, or 2; n is 〇, 1, 2, 158421.doc -19· 201216961 2 For any and all embodiments, the substituents are selected from the subgroups listed below. For example, 'in some embodiments, the lanthanide 〇Η. In some embodiments, the lanthanide _OR10. In some implementations In the example, 2 is _〇η, -〇ch3, or -OCH2CH3. In some embodiments, R6 is η, -CH3, F, or C. In some embodiments, R6 is Η. In some embodiments 'R7 is Η, -CH3, F, or C1. In some embodiments, R7 is Η. In some embodiments, R9 is Η, CVC6 alkyl, or (VCe fluoroalkyl. In some embodiments, R9 is only fluorene or fluorene. In some embodiments, R9 is Η. It should be understood that R3 may be present at any open position of the 坐n ring system. In some embodiments, 'each R3 is independently Halogen, C]-C4 alkyl, or C]-C4 fluorine Alkyl. In some embodiments, each R3 is independently F, c or -CH3. In some embodiments, each R4 is independently _, _CN, -oh, -〇R9, -S (=0 2R1(), C--C4 alkyl, C--C4 fluoroalkyl, CVC4 heteroalkyl, C, -C4 alkoxy, or C1-C4 alkoxy. In some embodiments, each R4 Independently dentate, -CN, -OH, -S(=0)2CH3, -S(=0)2CH2CH3, -ch3, -CH2CH3, -CF3, -CH2OH, -0CF3, -〇CH3, or -0 C H2 C H3. In some embodiments, each r4 is independently F, c J, -CN, -OH, -CH3, -CH2CH3, -CF3, -CH2〇H, -〇CF3, -OCH3 or -OCHzCH3 In some embodiments, each R4 is independently 1 or α. 158421.doc • 20· 201216961 In some embodiments C1-C4 fluoroalkyl. -ch3. 'R5 independently is halogen, Ci-Ci In some embodiments, each R5 is independently F, CM, or or in an embodiment, m is 〇 or 1. In some embodiments, the shank is 〇. In some embodiments, m is 1. In the embodiment, 'n is 0, 1, or 2. In some embodiments, η is 0. In some embodiments, η is 1. In some embodiments, η is 2. In some embodiments, Ρ is 〇 or 1. In some embodiments, ρ is 0. In some embodiments '15 is 1. In some embodiments, m is 〇; and ρ is 〇. In some embodiments, 2: is _〇H; R6 is η, _Ch3, ρ, or C1; R7 is Η, -CH3, F, or Cl; each R3 is independently a cyclin, C丨_C4 alkyl Or CrG fluoroalkyl; each R4 is independently _, _Cn, _〇H, -OR9, -S(=〇)2Ri〇, Ci_C4 alkyl, Ci_C4 alkyl, Ci_C4 heteroalkyl, q-C4 fluorine Alkoxylate, or Ci_C4 alkoxy; each rule 5 is independently halogen, Ci-C*alkyl, or fluoroalkyl; m is 〇 or 1; η is 0, 1, or 2; and ρ is 0 or 1. And R. Or C3-C6 cycloalkyl. In some embodiments, R2 is CVC4 alkyl, CVC4 fluoroalkyl, or Q-C4 lactalkyl. In some embodiments the 'R2 is a C1-C4 alkyl group. In some embodiments, r2 is -CH3'-CH2CH3'-CH2CH2CH3'-CH(CH3)2>-CH2CH2CH2CH3'-CH2CH(CH3)2, -CH2F, -CHF2, -CF3, -CH2CF3, -CD3, -CH2CD3, 158421.doc •21- 201216961 -CD2CD3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-W, or -CH2CH2-W; W-based hydroxyl, F, Cl, -CN, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, w is hydroxy, F, Cl, -CN, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R2 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH2F, -CHF2'-CF3'-CH2CF3'-CD3'- CH2CD3 '-CD2CD3 ' -CH2-W, or -CH2CH2-W e In some embodiments, R2 is -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CF3, -CD3, -CD2CD3, -CH2CD3 Or cyclopropyl. In some embodiments, R2 is -CH2CH3, -CH2CF3, -CD2CD3, or -CH2CD3. In some embodiments, R2 is -CH2CH3, _CD2CD3, or -CH2CD3. In some embodiments, R2 is -CH2CH3. In some embodiments, Z is -OH; R6 is Η; R7 is Η; m is 0; η is 0, 1, or 2; and ρ is 〇. In some embodiments, the compound of formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt thereof, or a cerium-oxide: 158421.doc

In some embodiments, each R3 is independently F, C1, or -CH3; each R4 is independently _-, -CN, -OH, -S(=0)2CH3, _S(=〇)2CH2CH3, -CH3 , -CH2CH3, -CF3, -CH2OH, -OCF3, -OCH3, or -OCH2CH3; -22- 201216961 Each R5 is independently F, Cl, or -CH3; m is 0 or l; n is 0, 1, or 2 ; and p is 〇 or 1. And R. CD2CD3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-W, or -CH2CH2-W; W-based hydroxyl, F, cn, -CN, -OCH3, -OCH2CH3, -0CH2CH2CH3, -OCH (CH3) 2, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl beta In some embodiments 'W-hydroxyl, F, Cl, -CN, cyclopropyl, cyclobutyl, cyclopentyl, Or cyclohexyl; each R4 is independently F, cn, -CN, -OH, -CH3, -CF3, -〇cf3, or ·〇Ch3; m is 〇; η is 〇, i, or 2; and p is 0. And R. CH2CH3; 4〇; _〇, i, or 2; and? Why? In some embodiments, the compound of formula (I) or formula (π) has the following structure, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof:

In some embodiments phenyl, 2-phenylphenyl, 3-phenylphenyl, 4-fluorobenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-di Fluorophenyl, 2,6-diphenylphenyl, 2-gasstyyl, 3-phenylphenyl, 4-phenylphenyl, 2,3-

158421.doc 23' S 201216961 Diphenyl, 2,4-diphenyl, 2,5-dichlorophenyl, 2,6-diphenyl, 2-bromophenyl, 3-bromophenyl , 4-bromophenyl, 2-methylphenyl, 3-mercaptophenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2 -nonyloxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-tri Fluorylphenyl, 3-trifluorodecylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4.methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-fluoro-3-phenylphenyl, 2-air-4-gas base, 2-n-5-oxyphenyl, 2-n--6-chlorophenyl, 2-gas- 3-gas base, 2-air-4-oxo group, 2-air-5-phenylene, 2- gas-6-amino group, 2-methyl-3-carbene group, 2-anthracene 4--4-phenylphenyl, 2-mercapto-5-chlorophenyl, 2-methyl-6-phenylphenyl, 2-methyl-3-fluorophenyl, 2-mercapto-4-IL benzene Base, 2-mercapto-5-fluorophenyl, 2-methyl-6-fluorophenyl, 3-mercapto-4-fluorophenyl, 2-trifluorodecyl-3-phenylphenyl, 2- Trifluoromethyl-4-chlorophenyl, 2-trifluorodecyl-5-phenylphenyl, 2-trifluoromethyl _6_chlorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxyindoleyl, 3-hydroxymethylphenyl, 4-hydroxydecylphenyl '2-oxime Alkylsulfonylphenyl, 3-hydrazinosulfonylphenyl, or 4-methylsulfonylphenyl. In some embodiments, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5- Difluorophenyl, 2,6-fluorobenzol, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2 , 5-dichlorophenyl, 2,6-diphenyl, 2-nonylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-tri Fluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-4-ylphenyl, 2-fluoro-3-chlorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro -5-gas phenyl, 2- 158421.doc -24- 201216961 Fluorine_6-chlorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5- Fluorophenyl, 2-gas-6-fluorophenyl, 2-methyl-3-chlorophenyl, 2-hydrazino-4-gas, 2-mercapto-5-phenyl, 2_han _6_chlorophenyl, 2_fluorenyl_3_fluorophenyl, 2-methyl-4-fluorophenyl, 2-mercapto-5-fluorophenyl, 2-methyl-6-fluorobenzene , 3-mercapto-4-fluorophenyl, 2-trifluoroindolyl-3-ylphenyl, 2•trifluoromethyl-4-phenyl, 2-trifluoromethyl-5-chlorobenzene Base, or 2_trifluoromethyl _6_gas phenyl. The invention encompasses any combination of the above groups for various variables. Throughout the specification, those skilled in the art will select their groups and substituents for stabilizing moieties and compounds. In some embodiments, the compound of formula (1) is a compound presented in Table i, or a pharmaceutically acceptable salt thereof, or an N-oxide: Table 1 Compound Name Structure LCMS* [M+H]+ 1 (Ε) Ethyl 3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-phenylbutan-1-ene) phenyl) acrylate 0 423 2 (Ε)-3 -(4-((Ε)-1-(1Η-oxazol-5-yl)-2-phenylbutan-1-en-1-yl)phenyl)acrylic acid 0 395 3 (E)-3-( 4-((E)-2-(4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 413 158421.doc -25 - 201216961 4 (E)-3-(4-((E)-2-(4-Phenylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)benzene Acrylic acid 0 429 5 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(3-decyloxyphenyl)but-1-ene- 1-yl)phenyl)acrylic acid 425 6 (E)-3-(4-((E)-2-(3-(hydroxy)phenyl)-1-(1)-indazol-5-yl) Butyl-1-en-1-yl)phenyl)acrylic acid U〇L〇h ο 425 7 (E)-3-(4-((E)-2-(4-(hydroxy)phenyl)phenyl)- 1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid kXr〇H 425 8 (E)-3-(4-((E)-2-(2- (hydroxymethyl)phenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 425 9 (Ε)-3- (4-((Ε)-1-(1Η-indazol-5-yl)-2-(o-tolyl)but-1-en-1-yl)phenyl)acrylic acid 409 10 (Ε)-3- (4-((Ε)-1-(1Η-oxazol-5-yl)-2-(m-decylphenyl)but-1-en-1-yl)phenyl)acrylic acid 0 409 11 (Ε)- 3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(p-phenylene)butan-1-ylidene-1)yl)phenyl)acrylic acid ΝρΛχ^〇Η 0 409 158421.doc 26- 201216961 12 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(2-methoxyphenyl)but-1- Alken-1-yl)phenyl)acrylic acid 425 13 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(4-decyloxyphenyl) But-1-en-1-yl)phenyl)acrylic acid i. 425 14 ((E)-3-(4-((E)-2-(2-Phenylphenyl)-1-(1H-)oxazol-5-yl)but-1-en-1-yl Phenyl)acrylic acid 0 429 15 (E)-3-(4-((E)-2-(3-chlorophenyl)-1-(1H-indazol-5-yl)but-1-ene- 1-yl)phenyl)acrylic acid ο 429 16 (E)-3-(4-((E)-2-(2-fluorophenyl)-1-(1H-indazol-5-yl)butane-1 -en-1-yl)phenyl)acrylic acid 0 413 17 (E)-3-(4-((E)-2-(3-fluorophenyl)-1-(1H-indazol-5-yl) But-1-en-1-yl)phenyl)acrylic acid ι/χ ο 413 18 (E)-3-(4-((E)-2-(2-ethylphenyl)_ 1_(1H-吲Oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 423 19 (Ε)-3-(4-((Ε)-1-(1Η-carbazol-5-yl)- 2-(2-(Trifluoromethyl)phenyl)but-1-en-1-yl)phenyl)acrylic acid 463 158421.doc -27- 201216961 20 (E)-3-(4-((E )-4-chlorocarbazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid ^COX^oh 〇429 21 (E)-3-(4-((E )-2-(2-cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 420 22 (E)-3-(4- ((E)-2-(2,4-Difluorophenyl)-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid ο 231 23 (E) -3-(4-((E)-2-(2-chloro-3-fluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)benzene )Acrylic "poxx^oH ο 447 24 (E)-3-(4-((E)-2-cyclopropyl-1-(1H-indazol-5-yl)-2-phenylvinyl) Phenyl)acrylic acid 0 407 25 (E)-3-(4-((E)-2-(4-fluoro-2-methylphenyl)-1-(1Η-indazol-5-yl))- 1-en-1-yl)phenyl)acrylic acid 0〇rF α 427 26 (Ε)-3-(4-((Ε)·2-(2,6-difluorophenyl)-1-(1Η- Oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 431 27 (Ε)-3-(4-((Ε)-2-(2,6-di-phenyl) -1-(1Η- °引σ坐-5-yl)丁-1· olefinic)phenyl)acrylic acid 9? 463 158421.doc -28 · 201216961 28 (E)-3-(4-((E -4,4,4-trimethyl-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid c^j〇νΡΧ〇^〇 η 0 398 29 (E)-3-(4-((E)-2-(4-fluoro-3-methylphenyl)-1-(1Η-indazol-5-yl)but-1-ene -1-yl)phenyl)acrylic acid 0 427 30 (E)-3-(4-((E)-2-(5-Ga-2-nonylphenyl)-1-(1Η-indazole-5) -yl)butyl-1- succinyl)phenyl)acrylic acid 427 31 (Ε)-3-(4-((Ε)-2-(2,3-difluorophenyl)-1- (1Η-carbazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid ςώ 0 431 32 (Ε)-3-(4-((Ε)-2-(2,5-二Fluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl) Acrylic acid fCrS^OH 431 33 (Ε)-3-(4-((Ε)-2-(2-chloro-5-fluorophenyl)-1-(1Η-indazol-5-yl))- 1-en-1-yl)phenyl)acrylic acid 0 447 34 (Ε)-3-(4-((Ε)-2-(2-chloro-6-methylphenyl)-1-(1Η-吲) Zyrid-5-yl)but-1-enyl)phenyl)propionic acid Jg O 443 35 (Ε)-3-(4-((Ε)-1-(7-chloro-1Η-carbazole-5) -yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid Cl o 429 158421.doc -29- 201216961 36 (E)-3-(4-((E)-l-( 4-methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)propanoate 〇409 37 (Ε)-3-(4-((Ε )-1-(7-fluorenyl-1H-σ丨°°-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid yO 409 38 (Ε)-3- (4-((Ε)-1-(6-methyl-1H-σ). Sodium _5_yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid SP 409 39 (Ε)-3-(4-((Ε)-1-(3-methyl- 1H-carbazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid yO ο 409 40 (Ε)-3-(4-((Ε)-1-(3 - gas-1H-carbazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid 0 429 41 (E)-3-(4-((E)-2- (4-Ga-2-methylphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid CXTC, «ροαΧ^οΗ ο 443 42 (Ε )-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid γΟ 0 381 43 (Ε) -3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-phenylindole-1-ylidene-1-yl)phenyl)acrylic acid 409 44 (E)-3- (4-((E)-2-(3-Cyanophenyl)-1-(111-°丨丨. sit-5-yl)but-1-en-1-yl)phenyl)acrylic acid 420 158421 .doc ·30· 201216961 45 (E)-3-(4_((E)-2-(4-cyanophenyl)-1-(1 Η-indazol-5-yl)but-1-ene- 1-yl)phenyl)acrylic acid hydrazine 420 46 (Ε)-3-(4-((Ε)-4-hydroxy-1-(1Η-indazol-5-yl)-2-phenylbut-1- Alken-1-yl)phenyl)acrylic acid Η°ν° ο 411 47 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-4-yloxy- 2-phenylbutan-1-lean-1-yl)phenyl)propene 0 425 48 (Ε)-3-(4-((Ζ.)-1-(1Η-indazol-5-yl)-3-decyloxy-2-phenylpropan-1-yl-1-yl) Phenyl)acrylic acid 0 411 49 (Ε)-3-(4-((Ε)-1-(4-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1 -yl)phenyl)acrylic acid 413 50 (Ε)-3-(4-((Ε)-1-(6-chloro-1H-indazol-5-yl)-2-phenylbut-1-ene- 1-yl)phenyl)acrylic acid 0 429 51 (Ε)-3-(4-((Ε)-1-(Ι H-carbazol-5-yl)-4-methyl-2-phenylpentane- 1-en-1-yl)phenyl)acrylic acid γ) 0 423 52 (Ε)-3-(4-((Ε)-1-(4-chloro-1H-indazol-5-yl)-2- Phenylbut-1-en-1-yl)phenyl)acrylic acid 429 53 (E)-3-(4-((E)-2-cyclopentyl-1-(1H-indazol-5-yl) -2-phenylvinyl)phenyl)acrylic acid OyO ηΡ〇ιΧΧυ〇η 0 435 158421.doc •31 - 201216961 54 (Ε)-3-(4-((Ε)-2-cyclohexyl-l-( 1 Η-carbazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid ΟγΟ 0 449 55 (Ε)-3-(4-((Ε)-1-(1Η-carbazole-5- ))-3-mercapto-2-phenylbutan-1-lean-1_yl)phenyl)acrylic acid 0 409 56 (E)-3-(4-((E)-3-cyclopropyl-1- (1H-carbazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid U) 421 57 (E)-3-(4-((E)-2-( 2-oxophenyl)-2-cyclopropylcarbazole-5- ) Vinyl) phenyl) acrylic acid A〇) «ΡΧΧΧ ^ ΟΗ 0 441 58 (Ε) -3- (4 - ((Ε) -1- (6- fluoro -1H- indole. Sodium-5-yl)-2-phenylbutyr-1-yl-1-yl)phenyl)acrylic acid i〇0(X^ ο 413 59 (Ε)-3-(4-((Ε)-1- (Ι H-carbazol-5-yl)-2-phenylhex-1-en-1-yl)phenyl)acrylic acid ΝΡυΧΧ^γ〇Η 0 423 60 (E)-3-(4-((E )-3-cyclopentyl-1-(1H-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid 449 61 (E)-3-(4- ((E)-2-(2-Ga-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 465 62 (Ε)-3-(4-((Ε)-1-(7-fluoro-1H-indolyl-5-yl)-2-phenylbutan-1-yl-1-yl)phenyl Acrylic acid F 0 413 158421.doc ·32· 201216961 63 (Ε)-3-(4-((Ε)-2-(2-chloro-4-fluorophenyl)-1-(1Η-吲. sitting - 5-yl)-4-methylpent-1-en-1-yl)phenyl)acrylic acid «PCXXX^OH 0 475 64 (E)-3-(4-((Z)-3,3-difluoro Oxazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid hydrazine 417 65 (E)-3-(4-((E)-2-(2-chloro-) 4-fluorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid οσρ F Ο 465 66 (E)-3-(4 -((E)-4-fluoro-1-(1H-indole-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid F\o 0 413 67 (E )-3-(4-((E)-4-chloro-2-(2-chloro-4-ft*phenyl)-1-(1Η- Σ3|σ sit-5-yl)but-1-en-1-yl)phenyl)acrylic acid °w 0 481 68 (Ε)-3-(4-((Ζ)-3,3,3-trifluoro -1-(1Η-indazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid FicJ〇0 69 (Ε)-3-(4-(( Ε)-1-(4_fluoro-1H-吲σ坐·5·yl)-2-(4-carb-2-indolylphenyl)buten-1-yl)phenyl)acrylic acid 445 70 (E )-3-(4-((E)-2-(4-chloro-2-methylphenyl)-1-(4-gas_111-° σ 坐-5-yl) But-1-ene -1-yl)phenyl)acrylic acid 461 71 (Ε)-3-(4-((Ε)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)-2- (4-fluoro-2-methylphenyl)ethenyl)phenyl)propene ____ 0 457 158421.doc ·33· 201216961 Acid 72 (E)-3-(4-((E)-2-( 4-ox-2-mercaptophenyl)-2- lysyl-1-(4-fail-1H-indazol-5-yl)vinyl)phenyl)acrylic acid 473 73 (Ε)-3- (4-((Ε)-1-(4-Ga-1Η-吲哇-5-yl)-2-(2-Ga-4-phenyl)but-1-en-1-yl)phenyl )Acrylic acid clCCrF ο 481 74 (E)-3-(4-((Z)-2-(2-Ga-4-fluorophenyl)-3,3-difluoro-1-(1H-indazole-5) -yl)prop-1-en-1-yl)phenyl)acrylic acid, <XrF "ΡσίΧγΟΗ 469 75 (E)-3-(4-((E)-2-cyclopropyl-1-(4) -fluoro-1H-indazole-5-yl)-2-phenyl B Yl) phenyl) acrylic acid 42576 NAI) -3- (4- (m--4- gas-1- (4-fluoro -1H-σ primer. Sodium-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid 0 447 77 (E)-3-(4-((E)-4-chloro-2-(2) - gas-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid c,tXTF 499 78 (E)-3 -(4-((E)-4-fluoro-2-(4-fluorophenyl)-1-(1Η~ °引σ坐-5-yl)but-1-en-1-yl)phenyl) Acrylic acid\£F Ο 431 79 (Ε)-3-(4-((Ε)-4-fluoro-1-(4-fluoro-lH-indazol-5-yl)-2-phenylbutan-l- Alken-1-yl)phenyl)acrylic acid 0 431 158421.doc -34- 201216961 80 (Ε)-3-(4-((Ε)-1-(1Η-carbazol-5-yl)-5-A Oxy-2-phenylpenta-l-thin-1.yl)phenyl)acrylic acid. - ϊ〇Λχ^〇η Ο 439 81 (Ε)-3-(4-((Ε)-1-(1Η-oxazol-5-yl)-6-decyloxy-2-phenylhex-l -en-1-yl)phenyl)acrylic acid 0 453 82 (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1Η-carbazole- 5-yl)-3-methylbut-1-en-1-yl)phenyl)acrylic acid 0 461 83 (Ε)-3-(4-((Ε)-1-(1Η-carbazole-5-) 2-(3-(trifluoromethoxy)phenyl)but-1-en-1-yl)phenyl)acrylic acid 479 84 (E)-3-(4-((E)-2- Cyclobutyl-1-(1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid 〇 851 85 (E)-3-(4-((E)-2-(2- Chloro-4-fluorophenyl)-2-3⁄4 butyl-1-(1Η·σ 引.-5-5-yl)vinyl)phenyl)acrylic acid 〇paF 473 86 (Ε)-3-(4-( (Ε)-1-(3-Fluoro-1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid 0 413 87 (E)-3-(4 -((E)-2-cyclobutyl-1-(3-murine-1Η-σ引. sit-5-yl)-2-phenylvinyl)phenyl)acrylic acid 0 439 88 (E)-3 -(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)benzene Acrylic acid 465 158421.doc -35- 201216961 89 (E)-3-(4-((E)-2-(2-Ga-4-fluorophenyl)-2-cyclobutyl-1-(3) -oxazol-5-yl)vinyl)phenyl)acrylic acid F 〇〇rF ο 491 90 (Ε)-3-(4-((Ε)-2-(4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl Ethyl acrylate ο 441 91 (Ε)-3-(4-((Ε)-1-(1Η-oxazol-5-yl)-2-(2-decyloxyphenyl)but-1-ene Ethyl-1-yl)phenyl)acrylate CO 453 92 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(4-decyloxybenzene) Ethyl buty-1-en-1-yl)phenyl)acrylic acid ο 453 93 (E)-3-(4-((E)-2-(3-Pheptylphenyl)-1-(1H) -0 丨 丨 坐 sitting -5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 411 94 (Ε)-3-(4-((Ε)-2-(2-hydroxyphenyl) )-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid CO "ΡΧΧΧ^ΟΗ 0 411 95 (Ε)-3-(4-((Ε) -2-(4-hydroxyphenyl)-1·(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid ο 941 96 (Ε)-3-(4-( (Ε)-2-(3-Butoxyphenyl)-Η1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid kXX〇. ο 467 158421.doc 36- 201216961 97 (E)-3-(4-((E)-2-(4-Butoxyphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)benzene Acrylic acid y〇r-«pXOu.oH 0 467 98 (Ε)-3-(4-((Ε)-1-(1Η-carbazol-5-yl)-2-(2-(methylsulfonate) Mercapto)phenyl)but-1-ene -1-yl)phenyl)acrylic acid 0 473 99 (Ε)-3-(4-((Ε)-1-(1Η-吲. Sodium-5-yl)-2-phenylbuty-1·lean-1 -yl)phenyl)-2-mercaptoacrylic acid yO ο 409 100 (Ε)-3-(4-((Ζ)-1- (1Η-carbazol-5-yl)-2-phenylbut-1-en-1-yl)-3-indolylphenyl)acrylic acid yO 409 101 (Ε)-3-(4-((Ε) -1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)-2-mercaptophenyl)acrylic acid 409 102 (Ε)-3-(4-(( Ζ)-1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)-2-phenylphenyl acrylate 429 429 103 (Ζ)-3-(4- ((Ε)-1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-propanuric acid 413 104 (Ζ)-3- (4-((Ε)-1-(1Η-oxazol-5-yl)-2_phenylbut-1-lean-1-yl)phenyl)-2-ylacrylic acid 0 429 105 (Ε)- 3-(4-((Ζ)-1-(1Η-indazol-5-yl)-2-phenylbut-1-en-1-yl)-3-lacylphenyl)acrylic acid 0 413 158421.doc -37- 201216961 106 (Ε)-3-(4-((Ζ)-1-(1Η-indazol-5-yl)-2-phenylbut-1-en-1-yl)-2- gas Phenyl)acrylic acid uO i9Crv^〇HF Ο 413 107 (Ε)-3-(4-((Ζ)-1-(1Η-carbazol-5-yl)-2-phenylbuty-1 -rare-1 -yl)-2·(trifluoromethyl)phenyl)acrylic acid 463 108 (Ε)-3-(4-((Ζ)-1-(1Η-indazol-5-yl)-2-phenylyl) -1-en-1-yl)-3-methoxy Acrylic acid COOCX^oh 1 ο 425 109 (Ε)-3-(4-((Ζ)-1-(1Η-indazol-5-yl)-2-phenylbutan-1- _-1) -2-oxooxyphenyl)acrylic acid 425 110 (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1Η-indazole-5) -yl)but-1-en-1-yl)phenyl)acrylate ethyl ester hydrochloride caF 0 475 111 (E)-3-(4-((E)-2-(2-chloro-4-fluoro) Phenyl)-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid C〇rF 0 447 112 (E)-3-(4-((E)- Ethyl 2-(2,4-dichlorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate ςχτ_ 0 491 113 (E)-3 -(4-((E)-2-(2,4-dichlorophenyl)-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid ατα 0 463 114 (E)-3-(4-((E)-2-(4-Gas-2-(trifluoromethyl)phenyl)-1-(1Η-indazol-5-yl)butan-1 -en-1-yl)phenyl)acrylic acid O 497 158421.doc -38 - 201216961 115 (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-2 -cyclopropylcarbazol-5-yl)vinyl)phenyl)acrylic acid 0 459 116 (E)-3_(4-((E)-2-(4-fluoro-2-(trifluorodecyl)benzene) ))-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid ο 481 117 (E)-3-(4-(l-(4-fluoro-1H) - carbazol-5-yl)-2-(4-fluoro-2 - (Trifluoromethyl)phenyl)butyl)phenyl)propionic acid 499 118 (E)-3-(4-((E)-2-(2,4-diphenyl)-1- (4-gas·1Η_α弓布坐-5-yl) But-1-ene-1·yl)phenyl)acrylic acid 481 119 (Ε)-3-(4-((Ε)-2-(4-chloro) -2-(Trifluoromethyl)phenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)propanoic acid Ρνχτα 0 515 120 ( E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-4-fluoro-1-(1H-indazol-5-yl)but-1-ene-1 -yl)phenyl)acrylic acid W. Npcax^〇H 465 121 (E)-3-(4-((E)-2-(2-chloro-4-methoxyphenyl)-1-(1Η- Oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid ςσ. , 0 459 122 (E)-3-(4-((E)-2-(2,4-dichlorophenyl)-4-fluoro-1-(4-fluoro-1H-indazol-5-yl) )but-1-en-1-yl)phenyl)acrylic acid; wc, 0 499 158421.doc -39- 201216961 123 (E)-3-(4-((E)-2-cyclopropyl-2- (2,4-diphenyl)-1-(4-fluoro-1H-indol-5-yl)vinyl)phenyl)acrylic acid F<XTC, 493 124 (E)-3-(4-( (E)-2-(2-Ga-4-fluorophenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylic acid 477 125 (E)-3-(4-((E)-2-cyclopropyl-2-(2;4-dichlorophenyl)-1-(1Η-indazol-5-yl)vinyl)phenyl Acrylic acid a〇tc, 475 126 (E)-3-(4-((E)-2-(4-Ga-2-ylphenyl)-2-cyclopropyl-1-(1H-carbazole) -5-yl)vinyl)phenyl)acrylic acid 455 127 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(2-methyl-5) -(Methylated sulfonyl)phenyl)butan-1-lean-1.yl)phenyl)propionic acid ο 487 128 (Ε)-3-(4-((Ε)-1-(1Η-吲 -5-5-yl)-2-(4-decyloxy-2-mercaptophenyl)but-1-en-1-yl)phenyl)propanoic acid 0 439 129 (E)-3-( 4-((E)-2-(2-Fluoro-4-decyloxyphenyl)-1-(1Η-σ?|.sodium-5-yl)butyl-1 -zil-1-yl) base ) propylene glycol O 443 130 (Ε)-3-(4-((Ε)-2-(2- gas-5-decyloxybenzene) )-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 459 158421.doc -40- 201216961 131 (E)-3-(4-((E -2-(2-Fluoro-4-(indolylsulfonyl)phenyl)-1-(1Η-indazol-5-yl)butyl-1-(phenyl-1-yl)phenyl)propanoic acid 00^ 491 132 (E)-3-(4-((E)-2-(2,4-Dichlorophenyl)-3,3,4,4,4-pentazol-5-yl) But-1-en-1-yl)phenyl)acrylic acid 0 468 133 (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(3-( Methylsulfonyl)phenyl)butan-1-ylan-1-yl)phenyl)propionic acid ο 473 134 (E)-3-(4-((E)-2-(2,4-di) Chlorophenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-ylidene-1-yl)phenyl)propionic acid cac, 481 135 (E)-3-(4- ((E)-2-(2-Chloro-3-indolylphenyl)-1-(11"1-0#11--5-yl)but-1-ene small group)phenyl)acrylic acid φ 0 459 136 (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-3,3,4,4,4-pentan-1-(1H-吲) .圭-5·yl)but-1-en-1-yl)phenyl) acrylate 452 137 (E)-3-(4-((E)-2-(4-chloro-2-cyanophenyl) -1-(1Η-η-oxazole-5-yl)but-1-en-1-yl)phenyl)acrylic acid N0Crc, 0 454 138 (E)-3-(4-((E)-2-( 2-cyano-4-fluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 438 158421.doc •41- 201216961 139 (E) -3-(4-((E)-2-(2-cyano-4-(trifluoromethyl)phenyl)-1-(1Η-indazol-5-yl)but-1-y-1 -yl)benyl)propionic acid LXrCFs ο 488 140 (E)-3-(4-((E)-2-(2-chloro-4-cyanophenyl)-1-(1Η-carbazole- 5-yl)but-1-en-1-yl)benzyl)acrylic acid 454 141 (E)-3-(4-((E)-2-(3-cyano-2-indenylphenyl) )-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 0 434 142 (E)-3-(4-((E)-2-(4- Cyano-2-mercaptophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid OCr"NO 434 143 (E)-3-(4 -((E)-2-(5-Cyano-2-methylphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 434 144 (E)-3-(4-((E)-2-(2-cyano-4-methoxyphenyl)-1-(1Η-indazol-5-yl)-but-1-ylide-1 -yl)phenyl)acrylic acid «ρσίΧγοΗ 450 145 (E)-3-(4-((E)-2- (2-Chlorophenyl) small (1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid 00 443 146 (E)-3-(4-( (E)-2-cyclobutyl-1-(1-indolyl-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid «ροαχ^οΗ 435 •42- 158421.doc 8 201216961 147 (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1-indolyl-1H-0) 丨-5-yl) But-1-en-1-yl)phenyl)propanoic acid C〇rF 461 148 (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1 -(1-(Difluoroindolyl)-1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)propionic acid 9〇rF 497 mass spectrometry data for the synthesis of compounds using standard synthetic techniques or The compounds of formula (I) described herein are synthesized using methods known in the art in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions presented herein may vary. The starting materials for the synthesis of the compounds of formula (I) are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, and the like. The compounds described herein, and other related compounds having different substituents, are synthesized using the techniques and materials described herein or other known techniques, including those found in the following documents: March, ADVANCED ORGANIC CHEMISTRY, 4th edition (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4th edition, volumes A and B (Plenum 2000, 2001); and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3rd edition, (Wiley 1999). The general method of preparing the compounds is modified as needed by introducing the various moieties found in the formulae provided herein using the appropriate reagents and conditions. In some embodiments, the compound of formula (I) is prepared as shown in the following reaction schemes. 158421.doc -43 - 201216961. Reaction Figure 1:

A protecting group is used to protect the nitrogen having an acidic proton in the compound of structure 1 to provide a compound of structure 2. In some embodiments, the protecting group is tetrahydro-2H-pyran (THP). In some embodiments, the conditions for nitrogen protection require 3,4-dihydro-2H-pyran (DHP), an organic acid, and a suitable solvent. In some embodiments, the organic acid is p-toluenesulfonic acid "bipyridinium (PPTS) or p-toluenesulfonic acid (p-TSA or p-TsOH) and the suitable solvent is dichloromethane. In some embodiments, the reaction is carried out at room temperature. Other conditions for protecting the nitrogen of the starting material are known. A detailed description of techniques suitable for the generation and removal of protecting groups is set forth in Greene and Wuts, Protective Groups in Organic Synthesis 5 3rd Edition, John Wiley & Sons, New York, NY, 1999; and Kocienski, Protective Groups, Thieme In Verlag, New York, NY, 1994, the disclosure is incorporated herein by reference. The structure 2 compound of the X-ray halogen or other suitable leaving group is reacted with a protected acetylene (e.g., trimethylmethanthine) under Sonogashira reaction conditions to provide the structure 3 compound. In some embodiments, 158421.doc •44- 201216961

The Sonogashira coupling reaction conditions include the use of a palladium catalyst and a copper halide salt beta. In some embodiments, the Sonogashira reaction conditions employ Pd(Ph3P)2Cl2, Cul, and triethylamine. In one embodiment, the reaction is carried out at about 8 °C. Other suitable reaction conditions are described in Rafael Chinchilla and Carmen Ndjera (2007). Chem. Rev. 107 (3): 874-922. The formazan protecting group of the structure 3 compound is removed under suitable reaction conditions to provide the structure 4 compound. In some embodiments, the strontium sulfate protecting group is removed in the sterol using carbonic acid unloading (K2C〇3). In other embodiments, the formazan protecting group is removed in tetrahydrofuran using tetrabutylammonium fluoride (TBAF). In some embodiments, the acetylene of structure 4 is reacted with r2_x under the conditions of the assay to prepare structural compound 5. In such cases, the rule 2 is a Cl_C6 alkyl group or a Ci-C6 fluoroalkyl group or a C"C4 alkoxy group or a Ci-C4 fluoroalkoxy group or a c3-C6 cyclodyl group, or the like, and the X system is suitably separated. Deprotection group. In some embodiments, the R2 moiety is loaded by other suitable conditions. In some embodiments, the compound of structure 2 is coupled with an alkynyl-trimethylsulfanyl or terminal alkyne under Sonogashira reaction conditions to provide Compounds of Structure 5. In some embodiments, the coupling of alkynyl-tridecyldecane to a compound of Structure 2 is comprised at a high temperature (e.g., about 80-90 ° C) in a suitable solvent (e.g., dimercaptoacetamide). Testing (eg, cesium carbonate), catalyst (eg, Pd(0Ac) 2, dppf), and copper-based salts (eg, Cul). In some embodiments, the coupling of a terminal alkyne to a compound of structure 2 is included at elevated temperatures (eg, About 8 〇 _ 120 ° C) The reaction was carried out using Pd(PPh3)2Cl2), Cul, and triethylamine. 158421.doc -45- 201216961 Reaction Figure 2:

The compounds of structures 5, 6 and 7 are then coupled together under suitable reaction conditions to provide the structure 8 compound. In some embodiments, suitable reaction conditions involve the use of an organometallic reagent. In some embodiments, suitable reaction conditions involve the use of a palladium catalyst. In some embodiments, suitable reaction conditions comprise the use of Pd(PhCN)2Cl2, K2C03 in dimercaptocaramine/water. Other suitable reaction conditions include those described in the following documents: Chengxiang Zhou and Richard C. Larock, Journal of Organic Chemistry, 2005, 70, 3765-3777; Chengxiang Zhou, Daniel E.

Emrich, and Richard C. Larock Organic Letters 2003, 1579-1582; Tsutomu Konno, Ken-ichi Taku, Takashi Ishihara, Journal of Fluorine Chemistry 127 (2006) 966-972 o then removes the protection of the structure 8 compound under suitable reaction conditions A group to provide a compound of structure 9. In some embodiments, suitable reaction conditions comprise the use of an acid. In some embodiments, suitable reaction conditions comprise performing the reaction at about 70 ° C using hydrochloric acid, ethanol. The ester group of the structure 9 compound is hydrolyzed to provide the carboxylic acid compound of structure 10 158421.doc -46 - 201216961. In some embodiments, the hydrolysis reaction comprises the use of lithium hydroxide in a mixture of tetrahydrofuran and ethanol. Other hydrolysis reaction conditions are known. In some embodiments, the compounds disclosed herein are prepared as shown in Reaction Scheme 3. Reaction Figure 3:

In some embodiments, the compound of structure 5 is reacted with the phenyl group of structure 6 and the boric acid of structure 11 under suitable reaction conditions to provide the structure 12 compound. In some embodiments, 'suitable reaction conditions include the use of an organometallic reagent. In some embodiments, a suitable organometallic reagent is a palladium catalyst. The aldehyde of the compound of structure 12 is then converted to the olefin under suitable reaction conditions to provide the structure 8 compound. Suitable reaction conditions include Homer-Wadsworth-Emmons olefination or Wittig olefination conditions. Alternatively, the compound of structure 5 can be reacted with a boronylating agent in the presence of a suitable catalyst to provide a compound of structure 13. In some embodiments, a suitable catalyst is an organometallic reagent such as a platinum catalyst. In some embodiments, the amount of catalyst affects the rate of reaction, but generally does not affect the yield or purity. In some examples, in a 158421.doc-47-201216961, the solvent has a minor effect on the reaction rate, but usually Does not affect the yield or purity. In some embodiments, the temperature has a significant effect on the rate of reaction, but generally does not affect the yield or purity. The Suzuki cross-coupling is then carried out using the structure 13 compound and the phenyl dentate of structure 14 to provide the structure 15 compound. In some embodiments, a 2 or 3 equivalent assay (e.g., Cs2C03) is used in Suzuki cross coupling. In some embodiments, 1.3 equivalents of base (eg, Cs2C03) are used in the Suzuki cross coupling. In some embodiments, the solvent has a significant effect on the rate and regioselectivity of the reaction. In some embodiments, dioxane, DME, or 2-MeTHF is used. In some embodiments, the water content has a significant effect on the rate and regioselectivity of this Suzuki cross-coupling. Subsequent Suzuki cross-coupling of the phenyl halide of Structure 5 and Structure 16 is then carried out to provide the structure 12 compound. A detailed description of the techniques applicable to the generation and removal of protecting groups is set forth in

Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, NY, 1999; and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1 994, the disclosure of which is hereby incorporated by reference. Other Forms of Compounds D Incorporated herein Where the compound of Formula (I) has one or more stereocenters, each center is independently present in the R or S configuration. The compounds presented herein contain all diastereomers, enantiomers, atropisomers, and epimers, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans 'sequence, transposition, ipsilateral, and ipsilateral isomers 158421.doc • 48· 201216961 and suitable mixtures thereof. If desired, stereoisomers are obtained by, for example, stereoselective synthesis and/or separation of the stereoisomers by chromatography on a palm column and/or using an optically active resolving agent. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, 1981. In certain embodiments, the compounds presented herein are present in the form of atropisomers. Atropisomeric systems refer to stereoisomers resulting from hindered rotation around a single bond, wherein the rotational spatial tension barrier causes the conformational isomerized. Atropisomers show axial to palmity. The atropisomer can be separated. In some embodiments, the atropisomers can be separated by a palmar resolution method (e.g., selective crystallization). The atropisomers are characterized by NMR or other suitable means of characterization as desired. The methods and compositions described herein comprise the use of amorphous forms as well as crystalline forms (also known as polymorphs). In one aspect, the compounds described herein are in the form of a pharmaceutically acceptable salt. Likewise, active metabolites of such compounds having the same type of activity are included within the scope of the invention. Further, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be the compounds disclosed herein. In some embodiments, the compounds described herein are formulated as prodrugs. "Prodrug" means an agent that can be converted into a parent drug in vivo. Prodrugs are usually used because in some cases they are easier to administer than parent drugs or have oral bioavailability or their parent drug in pharmaceutical compositions 158421.doc -49 - 201216961 improved Solubility. In some embodiments, examples of prodrugs designed to enhance effective water solubility are, but are not limited to, the compounds described herein, which are administered as esters ("prodrugs") but then undergo metabolic hydrolysis. Provide active entities. In certain embodiments, the prodrug is chemically converted to the biological, pharmaceutical or therapeutically active form of the compound after administration in vivo. In some embodiments, the site on the aromatic ring portion of the compound of formula (I) is susceptible to various metabolic reactions. Incorporating appropriate substituents on the aromatic ring structure will reduce, minimize or eliminate this metabolic pathway. In a particular embodiment, a suitable substituent (for example only) of a cycline, hydrazine or alkyl group that reduces or eliminates the susceptibility of the aromatic ring to a metabolic reaction. In another embodiment, the labeling is described herein in an isotope manner (eg, using a radioisotope) or by another means including, but not limited to, using a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label. Compound. In other or further embodiments, the compounds described herein are metabolized to produce a metabolite upon administration to an organism in need thereof, and then the metabolite is used to produce the desired effect (including the desired therapeutic effect). As used herein, "pharmaceutically acceptable" means that a material such as a carrier or diluent does not abrogate the biological activity or properties of the compound and is relatively non-toxic, that is, the material does not contain harmful substances after administration to the individual. Any of the components in its composition produces undesirable biological effects or interactions. The term "pharmaceutically acceptable salt" refers to a formulation of a compound which does not cause significant irritation to the organism to which it is administered and which does not eliminate the biological activity and properties of the compound. In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (1) with an acid 158421.doc • 50-201216961. A pharmaceutically acceptable salt is also obtained by reacting a compound of the formula (1) to form a salt. The compounds described herein are shaped and/or used as needed in the form of a pharmaceutically acceptable salt. The type of pharmaceutically acceptable salt includes, but is not limited to, / hexanoic acid caproic acid succinic acid addition salt formed by reacting a compound of the free base form with the following pharmaceutically acceptable ι , for example, hydrochloric acid, hydrobromic acid, mash · · · · metaphosphoric acid and the like; or organic acids, such as acetic acid, propionic acid, J pentoxide, glycolic acid, glycolic acid, lactic acid, malonic acid, glass Rhythmic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, benzoic acid, 3-(4-hydroxyphenylhydrazino)benzoic acid, cinnamic acid, dimethyl sulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, sulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-mercaptobicyclo-[2 2 2]octyl-2-ene-1-pyrene Acid, glucoheptonic acid, 4.4,-methylenebis(3-hydroxy-2-ene-2-indole-decanoic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate , gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid, and the like; (2) when present in Acid protons in the parent compound Metal ions (e.g., an alkali metal ion (e.g. lithium, sodium, 'potassium), alkaline earth metal ions (e.g. magnesium or calcium), or an ion Shao) salts formed when replaced. In some cases, the & described herein is coordinated with an organic test (such as, but not limited to) ethanolamine, diethanolamine 'triethanolamine, tromethamine, N-decyl glucosamine, two Cyclohexylamine, hydrazine (hydroxyindenyl) decylamine. In other instances, the compounds described herein form a salt with an amino acid such as, but not limited to, arginine, lysine, and the like. For the formation of a salt with a compound containing an acidic proton. _.doc, 51. 201216961 Acceptable inorganic bases include, but are not limited to, aluminum hydroxide, hydrogen hydroxide, potassium oxynitride, sodium carbonate, sodium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared in the form of an amine salt, a sodium salt, and other suitable amine acid salts. In some embodiments, the compounds provided herein are prepared as the sodium salt. In some embodiments, the compounds provided herein are prepared in the form of N-methyl glucosamine salt. In some embodiments, the compounds provided herein are prepared in the form of the hydrochloride salt. It will be understood that when referring to a pharmaceutically acceptable salt it includes a solvent plus formulation. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric solvent and forms a hydrate when formed into a solvent solvent water during the crystallization process with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Or when the solvent is an alcohol, an alcoholate is formed. Solvents of the compounds described herein are conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein are optionally present in unsolvated as well as solvated forms. The methods and formulations described herein comprise an oxide (right) and crystalline form of a compound having the structure of formula (1) (also known as Is a polymorph) or a pharmaceutically acceptable salt and an active metabolite of such compounds having the same type of activity. Certain Terms Unless otherwise stated, ^目丨丨"Jr rb *· Otherwise the following terms used in this application (including the specification and application: circumference) have the definitions given below. The singular form "heart _ (a and an)" and "the" used in the specification and accompanying application range 158421.doc •52· 201216961 includes a plurality of Nothing. Mass spectrometry, NMR, HPLC, protein chemistry, cockroaches, biochemistry, recombinant DNA techniques, and pharmacological methods are used unless otherwise stated. In the case of this application, the use of or "or" means "and/or" unless otherwise stated. In addition, the use of the term "including" and other forms (such as and "included") is not limiting. The headings of the sections used herein are for organizational purposes only and are not to be construed as limiting the subject matter. The alkyl group is a private aliphatic hydrocarbon group. An alkyl group is a saturated or unsaturated group. The base portion of the base is saturated or unsaturated with a bond or a linear chain, and the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl first butyl and second butyl. Group of bases. Typical alkyl groups include, but are in no way limited to, mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, pentyl, neopentyl, hexyl, allyl , vinyl, acetylene, but-2-enyl, butenyl, and the like. "Claw-based" means an alkyl group in which a hydrazine group or a plurality of argon atoms are replaced by hydrazine. The "alkoxy group" means an (alkyl) fluorene group, wherein the alkyl group is as defined herein. The term "cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl. The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, imine or iodine. The term "fluoroalkyl" means an alkyl group in which one or more hydrogen atoms are replaced by a fluorine atom. 158421.doc •53-201216961 The term "heteroalkyl" means that one or more of the backbone atoms are selected from atoms other than carbon (eg, oxygen, nitrogen (eg, -NH-, -N(alkyl) -), sulfur, or a combination thereof. In one aspect, a heteroalkyl-based Cl_c6 heteroalkyl group. The term "acceptable" as used herein with respect to a formulation, composition or ingredient means that there is no persistent detrimental effect on the overall health of the individual being treated. As used herein, the term "modulate" means directly or indirectly interacting with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target. The term "regulator" as used herein refers to a knife that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degrading agents, or combinations thereof. In a two-part embodiment, the sputum agent is an antagonist. In some embodiments, the modulating agent is a degrading agent. As used herein, "selective estrogen receptor modulator" or "SERM" refers to a molecule that differentially regulates the activity of estrogen receptors in different tissues. For example. In some embodiments, SERM shows £R antagonist activity in some tissues and er agonist activity in other tissues. In some embodiments, 'SERM shows ER antagonist activity in some tissues and no or minimal ER agonist activity in other, and woven. In some embodiments, 'SERM shows a booster activity in breast tissue, (four), woven, endometrial, woven, and/or cervical tissue, but shows minimal ER agonist activity in uterine tissue or There is no ER agonist activity. 158421.doc •54·201216961 The term "antagonist" as used herein, refers to a small molecule agent that binds to a nuclear hormone receptor and which is associated with an agonist-induced transcriptional activity of the nuclear hormone receptor. The term "agonist is used to bind to the nuclear hormone receptor and subsequently increases the small molecule agent of the nuclear hormone receptor transcriptional activity in the absence of a known agonist. The term "inverse agonist" as used herein. By the following, the small molecule agent 1 binds to the nuclear hormone receptor and then reduces the basal value of the nuclear hormone receptor transcriptional activity in the absence of a known agonistic heart. The term "degrading agent" as used herein refers to a small molecule that binds to fine (d) (d) (d) and subsequently reduces the steady-state protein content of the receptor. In some embodiments, the degradation agents described herein reduce the steady-state hormone receptor content by at least (10), at least 2%, at least present, or at least. At least 5〇%, at least 60. /. At least 65%, at least 7G%, at least 75%, at least 嶋, at least 85%, at least 90% or at least 950/〇. As used herein, the term "selective estrogen receptor degrading agent" or "S雠" refers to a small molecule agent that preferentially binds to an estrogen receptor and subsequently a lower steady-state estrogen receptor content than other receptors. The term "ER-dependent" as used herein refers to a disease or condition that does not occur or will not occur to the same extent in the absence of a snail receptor. The term "ER-mediated" as used herein refers to a disease or condition that does not occur in the absence of a hormone receptor but can occur in the presence of an estrogen receptor. As used herein, the term "ER sensitivity" refers to a disease or condition that does not occur, or does not occur to the same extent, in the absence of a hormone, 158421.doc -55-201216961. The term "cancer" as used herein refers to abnormal cell growth that tends to proliferate in an uncontrolled manner and in some cases metastasize (diffuse). Types of cancer include, but are not limited to, solid tumors (eg, tumors of the following tissues: bladder, intestine, brain, breast, endometrium, heart, kidney, lung, uterus, lymphoid tissue (lymphoma), ovary, gonad, or other Endocrine organs (disegic glands), prostate, skin (melanoma or basal cell carcinoma) or hematological tumors (such as leukemias and lymphomas) at any stage of the disease with or without metastasis. Other non-limiting examples of cancer include acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, rectal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdomyolike tumor, basal cell carcinoma, cholangiocarcinoma , bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumor, brain and spinal cord tumor, breast cancer, bronchial tube tumor, Burkitt lymphoma, cervical cancer, Chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell tumor, embryonal tumor, endometrial cancer, ependymoma, ependymoma, esophageal cancer , Ewing sarcoma family tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal tract Stromal cell tumor, blastoma, glioma, hairy cell leukemia, head and neck cancer, hepatocyte (liver) cancer, hodgkin lymphoma, hypopharyngeal carcinoma, Endometrial carcinoma, islet cell tumor (endocrine membrane gland), Kaposi sarcoma, kidney 56·158421.doc 201216961 cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia 'liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, He Jiejin's lymphoma, non-Hodgkin's lymphoma, lymphoma, Waldenstrdm macroglobulinemia, medulloblastoma, myeloma, melanoma, mesothelioma, oral cancer, chronic myeloid white Disease, myeloid leukemia, multiple myeloma, nasopharyngeal carcinoma, neurocytoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma, ovary Cancer, ovarian epithelial cancer, ovarian germ cell tumor, low-grade ovarian potential tumor, pancreatic cancer, papillomatosis, parathyroid carcinoma, penile cancer, pharyngeal cancer, intermediate differentiation Pineal parenchyma, pineal blastoma, and opioid primitive neuroectodermal tumor, pituitary tumor, plasma cell tumor/multiple myeloma, pleural pulmonary blastoma, primary central nervous system lymphoma, prostate cancer , rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, tumor of Ewing's sarcoma family, sarcoma, Kaposi's sarcoma, Sezary syndrome, skin Cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, gastric cancer (gastric cancer), opioid primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus Cancer, squamous adenocarcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrdm macroglobulinism, Wilms tumor. 'The term "co-injection" or the like as used herein is intended to cover the administration of a selected therapeutic agent to a single 158421.doc •57·201216961 patient's and is intended to include the same or different routes of administration or at the same or different times. Invest in the treatment plan. The term "effective amount" or "therapeutically effective amount" as used herein means an amount of the agent or compound administered to reduce the symptoms or conditions of the disease or condition being treated to a certain extent. The result includes reducing and/or alleviating the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, for therapeutic use, an "effective amount" is a condition which provides a significant reduction in the symptoms of the disease, including the compositions of the compounds disclosed herein. The appropriate "effective amount" in any individual case is determined using techniques such as a dose escalation study as needed. The term "pharmaceutical combination" as used in the present invention means a product produced by mixing or combining more than one active ingredient, and comprising both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredient (e.g., the compound of formula (1)) is administered to the patient simultaneously with the auxiliary agent in the form of a single entity or dosage. The term "unfixed combination" means that the active ingredient (eg, a compound of formula (1)) and the co-agent are administered to the patient as separate entities simultaneously, in parallel or sequentially and without specific time-limited restrictions, wherein the administration is in the patient The effective concentration of the two compounds is provided. The latter also applies to cocktail therapy, e.g., administration of three or more active ingredients. The "metabolite" of a compound disclosed herein is a derivative of the compound formed upon metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound formed by the metabolism of a compound. As used herein, the term "metaphoric" refers to the sum of the processes by which an organism changes a particular species, including but not limited to hydrolysis reactions and reactions catalyzed by enzymes. Therefore, the enzyme allows the compound to produce a specific structural change in 158421.doc •58·201216961. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while urinary bud diphosphate glucoside transferase catalyzes the transfer of glucosamine acid molecules to aromatic alcohols, alcohols, acid, amines, and free sulfur. On the hydrogen base. The metabolites of the compounds disclosed herein are optionally treated by administering the compound to a host and analyzing a tissue sample from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. The term "individual" or "patient" encompasses a mammal. Examples of mammals include, but are not limited to, humans, chimpanzees, baboons, monkeys, cats, horses, sheep, goats, pigs, rabbits, dogs, juveniles, mice, mice, and the like. In one aspect, the mammal is a human. The term "treatment" ("_", "" (or "treatment") as used herein, includes alleviating, attenuating or ameliorating at least one symptom of a disease or condition, preventing other symptoms, inhibiting disease or greenness, for example, preventive and/or Or therapeutically preventing the progression of a disease or condition, alleviating a disease or condition, causing the disease or condition to subside, reducing the condition caused by the disease or condition, or terminating the symptoms of the disease or condition. And routes include, but are not limited to, oral, parenteral (intravenous, subcutaneous, intramuscular), intranasal, frequency, local, rectal, aerosol, eye lung, transmucosal, transdermal, vaginal, ear, nasal And local administration. This is only an example and f 'parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection and inward, direct ventricular, intraperitoneal, intralymphatic, intranasal and intranasal Injection. In certain embodiments, the compounds described herein are administered systemically. In certain other embodiments, the compounds described herein are 158421.doc • 59·201216961. Pharmaceutical combination /Formulations In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert ingredients, which are advantageous for the pharmaceutically acceptable inert ingredients. The active compound is treated as a pharmaceutical preparation. Suitable formulations depend on the chosen administration. For an overview of the pharmaceutical compositions described herein, see, for example: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Company' Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. Editor, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY·, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott

Williams & Wilkins 1999) 'This disclosure is incorporated herein by reference. A pharmaceutical composition as used herein refers to a mixture of a compound of formula (1) with other chemical components (i.e., pharmaceutically acceptable inert ingredients), such as carriers, excipients, binders, Fillers, suspending agents, flavoring agents, sweeteners, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, A wetting agent, antifoaming agent, antioxidant, preservative, or a combination thereof. Pharmaceutical compositions facilitate the administration of compounds to mammals. 158421.doc _ 60 · 201216961 The pharmaceutical composition comprises at least one compound of formula (i), or a pharmaceutically acceptable salt thereof, as the active ingredient in the form of the free acid or free base or in the form of a pharmaceutically acceptable salt. Furthermore, the methods and pharmaceutical compositions described herein comprise the use of N-oxides (if appropriate), crystalline forms, amorphous phases, and active metabolites of such compounds having the same type of activity. In some embodiments, the compounds described herein exist as unsolvated forms or as solvates with pharmaceutically acceptable solvents such as water, ethanol, and the like. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions 'liposome dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, instant formulations. , lozenges, capsules, pills, delayed release formulations, extended release formulations, intestinal > cereal coated formulations, pulsed release formulations, multiparticulate formulations, and mixed formulations of immediate release and controlled release . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered systemically. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof, is orally administered. All orally administered formulations are suitable for the administration of the present invention. The solid dosage forms disclosed herein are in the form of tablets, pills, powders, capsules, solid dispersions, solid solutions, Bioavailable dosage forms, controlled release formulations, pulsed release dosage forms, multiparticulate dosage forms, beads, precipitates, particles. In other embodiments, the pharmaceutical formulation is recorded in the final form. In other embodiments, the pharmaceutical formulation is in the form of a bond. In other embodiments, the pharmaceutical formulation is in the form of a suspension I58421.doc • 61 · 201216961 Lozenges, instant tablets, bite-disintegrating tablets, rapid collapse Lozenges, effervescent tablets, or caplets. In other embodiments, the composition is in the form of a capsule. In some embodiments, a pharmaceutical solid oral dosage form is formulated to provide controlled release of the active compound. Controlled release features include, for example, sustained release, extended release, pulsed release, and delayed release characteristics. In one aspect, the liquid formulation for oral administration is in the form of an aqueous suspension selected from the group consisting of, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, Gel, and syrup. See, for example, 'See Singh et al.' Encyclopedia of Pharmaceutical Technology, 2nd Edition, pp. 754-757 (2002). For buccal or sublingual administration, the compositions may be in the form of a conventionally formulated lozenge, lozenge, or gel. In one aspect, the compound of formula (1), or a pharmaceutically acceptable salt thereof, is formulated into a pharmaceutical composition suitable for intramuscular, subcutaneous, or intravenous injection. Parenteral injection involves a bolus and/or continuous infusion. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof, is administered intravenously. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof, is administered subcutaneously. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof, is administered topically. In such embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is formulated into a variety of compositions for topical administration, such as solutions, suspensions, lotions, gels, lotions, shampoos. , scrubbing solution, coating solution, smear, music stick, drug bandage, balm, cream or ointment. In some embodiments, the compound of formula (1), or a pharmaceutically acceptable salt thereof, is topically administered to a mammalian skin, and the compound of formula (1) is formulated into a transdermal dosage form. Another aspect is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of estrogen receptor activity which causes pathology and/or symptoms of a disease or condition A disease, condition or condition. In one aspect, the disease or condition is any one of the diseases or conditions specified herein. Administration Method and Treatment Protocol In one embodiment, a compound of formula (1), or a pharmaceutically acceptable salt thereof, is used to prepare a medicament for treating a disease or disease in a mammal that benefits from a decrease in estrogen receptor activity shape. A method of treating any of the diseases or conditions described herein in a mammal in need of such treatment comprises administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable amount thereof a salt, an N-oxide, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate). The therapeutically effective amount will depend on the severity of the disease or condition and the course of the disease, the prior art, the condition of the patient, the weight, and the response to the drug, and the judgment of the treating physician. The therapeutically effective amount is determined, if desired, by methods including, but not limited to, escalating clinical trials. In any of the methods of treatment described herein, an effective amount of a compound of formula (1) is: (a) administered systemically to a mammal; and/or (b) orally administered to a mammal; and/or (c) Intravenous administration to a mammal; and/or (d) administration by injection into a mammal, and/or (e) topical administration to a mammal; and/or (f) non-systemic or local administration of breastfeeding animal. 158421.doc -63- 201216961 In some cases, the treatment consists of a single administration of an effective amount of a compound, including other examples, wherein τ (0 is administered once to the compound; (1)) is administered to the mammal within one 曰Repeatedly with the servant; (ni) uninterrupted; or (IV) continuous administration. Any of the above aspects are exemplified by other embodiments in which a plurality of compounds are administered in an effective amount, including other embodiments thereof, wherein (1) it is administered continuously or intermittently in a single dose. (11) The time between multiple administrations is every 6 hours; (out) every 8 hours, the compound is administered to the animal, and (iv) the compound is administered to the mammal every 12 hours. (v) The mother administered the compound to the mammal for 24 hours. In other or alternative embodiments, the method comprises a rest period in which the administration of the compound is temporarily discontinued or the dose of Compound 2 administered is temporarily lowered; at the end of the drug holiday, the compound is re-opened + τ. In one embodiment, the length of the drug holiday is from 2 days! Years vary. In the case where the patient's condition has not been improved, the patient is administered with a long-term (i.e., extended time) according to the doctor's advice. In certain embodiments in which the patient's condition has improved, the dose of the administered drug is temporarily reduced or temporarily interrupted for a certain length of time (i.e., "drug holiday"). In some embodiments, The dose range for adult treatment is usually 〇〇1 called -5000 mg/day. In one aspect, the dosage for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the dosage is conveniently provided in a single dose of 1 divided doses administered simultaneously or at appropriate intervals, such as 2, 3, 4 or more divided doses per day. In one embodiment, the hydrazine dose suitable for the compound of formula (I), or a pharmaceutically acceptable salt thereof, is from about J5842l.doc 64.201216961 0.01 to about 50 mg/kg/body weight. Combination Therapy In some cases 'appropriate combination administration of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents. In certain embodiments, the pharmaceutical composition further comprises One or more anticancer drugs. In a specific embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second therapeutic agent, wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a first treatment are co-administered The different conditions of the disease, disorder or condition treated by the agent, thereby providing greater overall benefit than when the agent is administered alone or in combination with any of the therapeutic agents. In either case, regardless of the disease, condition or condition being treated, the overall benefit experienced by the patient is the additive effect of the two therapeutic agents, or the patient may experience a synergistic benefit. 4 In combination therapy, multiple therapeutic agents are administered in any order or even simultaneously (one of which is one of the compounds described herein). If the same disk, by way of example only, is to provide a plurality of therapeutic agents in a single, uniform form or in multiple forms (e.g., a single pill or as two separate pills). ', · In some embodiments, 'an estrogen receptor-dependent or estrogen-like condition or disease (eg, a proliferative disorder, including cancer) A" includes administering a compound of formula (1) to a mammal, or a pharmaceutical thereof Upper:: A combination of at least one other therapeutic agent. Salts of & In some embodiments, the compound of formula (1), or a combination thereof, is combined with a hormone blocking therapy, a chemical method, and a salt. , or 158421.doc -65 - 201216961 In some embodiments, at least one other therapeutic agent used in combination with a compound of formula (i), or a pharmaceutically acceptable salt thereof, comprises one or more of the following: Abiraterone, abarrelix, adriamycin, actinomycin, acivicin, aclarubicin, acoda hydrochloride « Acodazole hydrochloride, acronine, adozelesin, aldesleukin, alesumuzumab, another 'allopurinol', alli Alitretinoin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, aminolevulinic acid, amine Filled with amifostine and ampoules. Amsacrine, anastrozole, anthramycin, aprepitant, erbium tetroxide, aspartate, asperlin, aspergillus Azacitidine, azatepa, azotomycin, batimastat, bendamustine hydrochloride, benzodepa, shellfish Favacizumab, bexarotene, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin ), bleomycin, bleomycin sulfate, bortezomib, brequinar sodium, bropirimine, busulfan, actinomycin c (cactinomycin), caprotestosterone 158421.doc •66· 201216961 (calusterone), calacetamide, carbetimer, carboplatin, carmustine, hydrochloric acid card Carubicin hydrochloride Carzelesin, capecitabine, cedefingol, cetuximab, chlorambucil, cirolemycin, Cisplatin, cladribine, clofarabine, cristatol mesylate, cyclamin, cytarabine, dacarbazine , dasatinib, daunorubicin hydrochloride, dactinomycin, darbepoetin alfa, decitabine, degarelix ), denileukin diftitox, dexormaplatin, dexrazoxane hydrochloride, dezaguanine, leucovorin, and diaziquone ), docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, Dazo Duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, eltrombopag olamine, enloplatin, enpu Enpromate, epipropidine, epirubicin hydrochloride, afaribin; epoetin alfa, erbulozole, erlotinib hydrochloride, Isoprozin hydrochloride 158421.doc -67- 201216961 (esorubicin hydrochloride), estramustine, estramustine, etanidazole, etoposide, acid-based support Bovine glycoside, etoprine, everolimus, exemestane, fadrozole hydrochloride, fazarabine, fendi Fenretinide, Hlgrastim, floxuridine, fludarabine phosphate, I fluorouracil, flurocitabine, quinolone (fosquidone), forsked sodium (fost Riecin sodium), fulvestibine, gefitinib, gemcitabine, gemcitabine hydrochloride, gemcitabine-cisplatin, gemtuzumab ozogamicin, goserelin acetate , histrelin acetate, hydroxyurea, idarubicin hydrochloride, ifosfamide, iimofosine, temimozumab (Imofosine) Ibritumomab tiuxetan), idarubicin, isocyclic guanamine, imatinib mesylate, imiquimod, interleukin 11 (containing recombinant interleukin II, or rlL2), interferon a-2a, interferon a-2b, interferon α-ηΐ, interferon α-η3, interferon β-la, interferon γ-lb, iproplatin, irinotecan hydrochloride (irinotecan hydrochloride), ixabepilone, lanreotide acetate, lapatinib, lenalidomide, and koji. Sit, leuprolide acetate, leucovorin calcium, acetaminophen 158421.doc -68- 201216961 Ruilin, Zuoweimi. Levamisole, liposomal cytarabine, liarozole hydrochloride, lometrexol sodium, lovastatin, lomustine, loxophone hydrochloride Losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, Melphalan, menogaril, mercaptopurine, methotrexate, methotrexate, methoxsalen, methotrexate (metoprine) ), meturedepa, mimitomoide, m ito care in, mitocromin, mitogilin, mitoxantine (mitomalcin), mitomycin C (mitomycin C) mitosper (mitosper), mitotane (mitotane), mitoxantrone hydrochloride, mycophenolic acid, styrene-acrylic acid Sodium nandro Lone phenpropionate), nelarabine, nilotinib, nocodazoie, nofetumomab, nogalamycin, orfamumab (ofatumumab) ), oprelvekin, ormaplatin, oxaliplatin, oxisuran, paclitaxel, palifermin, palo hydrochloride Palonosetron hydrochloride, pamidronate, pegfilgrastim, pemetrexed disodium, 158421.doc -69- 201216961 pentostatin, Panitumumab, pazopanib hydrochloride, pemetrexed diazepam, plerixafor, pralatrexate, pegaspargase, Peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, Hydrochloric acid ° piroxantrone Hydrochloride), plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine Hydrochloride, puromycin, puromycin hydrochloride, pyrazofurin, quinacrine, raloxifene hydrochloride, Rabburicase, recombinant HPV bivalent vaccine, recombinant HPV tetravalent vaccine, riboprine, rogletimide, rituximab, romidepsin Romidepsin), romiplostim, saHngol, safingo, sargramostim, semustine, simtrazene, cyprus T (sipuleucel-T), sorafenib (sorafenib), sodium sparfosate sodium 'sparsomycin.', spirogemianium hydrochloride, spirulina; Ding (spiromustine), screw Spiroplatin), streptonigrin, streptozocin, sulofenur, sunitinib malate 158421.doc -70- 201216961 (sunitinib malate), thalimycin ( Talisomycin), tamoxifen citrate, tecogalan sodium, tegafur, teloxantrone hydrochloride, temo. Temozolomide, temoporfin, temsirolimus, teniposide, teroxirone, testolactone, thalidomide (thahdomide), sulfur, thiamiprine, thioguanine, thiotepa, thiophene, tiazofurin, tirapazamine, hydrochloric acid Topotecan hydrochloride, toremifene, tositumomab, and I 131硪 tocilizumab, trastuzumab, trestolone acetate, Tretinoin, triciribine phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, hydrochloric acid Chlorine (tubulozole hydrochloride), urine. Uracic mustard, uredepa, valrubicin, vapreotide, verteporfin, vinblastine, vinca sulfate Vinblastine sulfate), vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, sulfuric acid epoxide Vinilrosine sulfate, vinorelbine tartrate, vinrosidine sulfate, vindrodine sulfate (vinzolidine 158421.doc -71- 201216961 sulfate), vorinostat (v〇rin〇) Stat), chloroplatin (v〇r〇z〇ie), zeniplatin, zinostatin, zoledronic acid, and zorubicin hydrochloride (z〇) Rubicin hydrochloride). In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, and an antiemetic agent are used in combination to treat beta nausea or beta vomiting derived from the use of a compound of formula (1), an anticancer drug, and/or radiation therapy. In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, and an agent for treating anemia or neutropenia are used in combination. In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, is administered with a corticosteroid. In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, is co-administered with an analgesic. In some embodiments, a compound of formula (1), or a pharmaceutically acceptable salt thereof, and radiation therapy or radiotherapy are used in combination. Radiotherapy uses ionizing radiation to treat cancer and other diseases. Radiation therapy is used as needed to treat local solid tumors such as cancer of the skin, tongue, throat, brain, breast, prostate, colon, uterus and/or cervix. It is also used as needed to treat leukemias and lymphomas (the cancers that form the blood cells and the lymphatic system, respectively). The technique used to deliver radiation to cancer cells directly places the radioactive implant in a tumor or body cavity. This is called internal radiotherapy (brachytherapy, interstitial irradiation, and intraluminal irradiation). Using internal radiation therapy, the radiation dose is concentrated in a small area and the patient is in the hospital. Stay for a few days. Internal radiation therapy is commonly used for tongue, uterus, and cancers of the first gland, colon, and cervix. The term "radiotherapy" or "ionizing radiation" encompasses all forms of I!, including but not limited to alpha, p, and fluorescing and ultraviolet light. Stomach Examples These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims. Example 1: 5-Bromo-1-(tetrahydro-2H-pyran-2-yl)_ih-carbazole (Preparation of intermediate oxime to a magnetic stir bar, rubber septum, and & inlet 25 〇 The _mL round bottom flask was charged with 5-bromo-1H-carbazole (10 g, 50.7 mmol) and anhydrous DCM (101 mL). To this solution was added 〇ηρ (23 mL, 253.8 mmol) at room temperature. Then, PPTS (1.28 g, 5 mmol) was added. The mixture was stirred at room temperature for 48 h. After completion of TLC, the reaction mixture was quenched with water and extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by EtOAc EtOAc EtOAc The title compound (13 g) was obtained as a pale yellow oil. NMR (300 MHz, DMSO-d6): δ 8.10 (s, 1 Η), 8.02 (d, lH), 7.73 (d, lH), 7. lH), 5.86 (dd, lH), 3.89-3.85 (m5 1Η), 3.73-3.69 (m, 1H), 2.43-2.31 (m, 1H), 2.06-192 (m, 2H), 1.80-1.64 (m, 1H), 1.60-150 (m, 2H). Example 2: 5-ethynyl-1-(tetrahydro-2) Preparation of H-pyran-2-yl)-1Η-carbazole (Intermediate 2) 158421.doc •73- 201216961 Step 1: 1-(tetrahydro-2H-pyran-2-yl)-5-( (trimethylformamidinyl)ethynyl)-1Η-carbazole

Add 5-iso-1-(tetrahydro-2H-"bi-2-yl)-1Η-carbazole to a 25 0-mL pressure tube (11.9 g '42.3 mmol; intermediate 1), Pd (Ph3P) 2Cl2 (1.48 g, 0.05 mmol), Cul (0.8 g, 4.2 mmol) and THF/triethylamine (5:1, 85 mL) «Degas the mixture using three vacuum/N2 cycles and then add Sankenji Jiashi Xiyuan Jiji Express (9 mL, 63.5 mmol). The pressure tube was sealed and heated at 80 ° C for 2 days. After the LCMS was completed, the reaction mixture was cooled to room temperature and then was transferred from Celite (EtOAc) The condensate was passed to obtain the crude product which was used directly in the next step. LCMS: 299 (M+H)+. Note: For this compound and other compounds synthesized using this reaction, an amine (e.g., triethylamine or gepirite) is used as a solvent alone to employ an alternative procedure. Step 2 · 5_B-Block-1-(Tetrazo- 2H-Wlfc-Bing-2-yl)-1Η-η丨丨

A 250-mL round bottom flask equipped with a magnetic stir bar, a rubber septum, and an A inlet was charged with 1-(tetrahydro-2H-pyrrole_2.yl)_5· (triterpene) in MeOH. A solution of the germyl) ethynyl)-1 - oxazole (12.6 g, 42.2 mmol). To this solution was added solid K2C03 (0.58 g, 4.2 158421.doc •74·201216961 mmol) in one portion. The resulting mixture was stirred at room temperature for 4 h. After the completion of the EtOAc, EtOAc (3 g, m. 〇mhz, DMSO-d6): δ 8.13 (s, 1H), 7.96 (s, 1H), 7.75 (d, 1H), 7.47 (dd, 1H), 5.86 (dd, 1H), 4.10 (s, 1H) , 3.90-3.86 (m5 1H), 3.78-3.68 (m, 1H), 2.43- 2.32 (m, 1H), 2.06-1.93 (m, 2H), 1.81-1.66 (m, 1H), 1.60- 1.50 (m , 2H). Example 3 · 5-( But-1-Decision _i_yl)-i_(tetrazol-2-yl)-lH-〇5| Preparation of Saliva (Intermediate 馊3)

A 250-mL round bottom flask equipped with a magnetic stir bar, a rubber septum, and a N2 inlet was charged with 5-ethynyl-1-(tetrahydro-2H-°pyran-2-yl)-1Η-吲 ( 4.2 g, 18.6 mmol; intermediate 2) and anhydrous THF/TMEDA (9:1, 93 mL). This solution was cooled to -78 ° C in an IPA / dry ice bath and n-BuLi (17.4 mL hexanes, 27.84 mmol) was added dropwise over 15 min. The resulting mixture was stirred at -78 °C for 30 minutes, and then ethyl iodide (2.23 mL, 27.84 mmol) was added dropwise over 5 min. The mixture was gradually warmed to room temperature, stirred for 1 h, and then heated at 40 ° C overnight. After completion of LCMS, the reaction mixture was cooled to room temperature, quenched with water (1 mL) and extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (100 mL), washed with brine (5 mL) <[<"&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 0-1 〇% ethyl acetate) purification

The title compound (1.42 g) was obtained as a pale yellow solid. NMR (300 MHz, DMSO-de): δ 8.08 (s, 1 Η), 7.82 (s, 1H), 7.69 (d, 1H), 7.39 (d, 1H), 5.84 (dd, 1H), 3.89-3.86 ( m, 1H), 3.76- 3.72 (m, 1H), 2.45-2.36 (m, 3H), 2.04-1.94 (m, 2H), 1.74 (m,1H), 1.57-1.20 (m, 2H), 1.16 ( t, 3H); LCMS: 255 (M+H)+. Note: For this compound and other compounds prepared using this reaction, lithium bis(trimethylmethanealkyl) guanamine has been used as a base in THF at 0 ° C followed by the use of alkyl dentate under reflux. Alkylation. The intermediates in Table 2 were prepared from known or commercially starting materials according to the procedure indicated for Intermediate 1-3. Table 2.

Intermediate 4 1-(tetrazo-2H-.pyran-2-yl)·5-(4,4,4-triazol-1-yn-1-yl)-1Η-carbazole<ΧΓ ΤΜ^ Intermediate 5 5-(丁-1-快-1·yl)-7-气·1·(Four gas·2Η-. 喊—基基)-1 Η-ϋ弓卜坐ΤΗΡ X Middle 鳢6 5-(丁-1-快-1-yl)·7-methyl-1-(tetraqi-211-°pyran-2-yl)-111-17丨11 sitting NpX ΤΗΡ 1 Intermediate 7 5 -(丁-1-快-1-yl)-3-methyl· 1-(tetrahydro·21^-° ratio °N-2-yl)-111-11 〇 〇 sitting THP intermediate 8 5-( Ding·1_快_1·基)-3-气-1-(Four gas·21^-11 than -2--2-yl)-111-°丨? Sitting on 'M-0 THP 158421.doc •76· 201216961 Intermediate 9 5-(Pro-1_blocky) small (tetrahydro-2Η-mouth ratio-2-yl)-1 Η·1. Sitting ΤΗΡ Intermediate 10 5-(pent-1-yne-1-yl) small (tetrahydro-2Η> ratio °N-2-yl)-1Η-® bow|saliva Intermediate 11 5-(full deuteration Butyr-1·yn-1-yl)small (tetrahydro-2-indole-pyran-2-yl)-1Η-carbazole-C〇aCD, 实例 Example 4: 5-(but-1-yn-1-yl) Preparation of 4-methyl-1-(tetrahydropyran-2-yl)-1H-indazole (Intermediate 12) Step 1: 4-methyl-1-(tetrahydro-2H-pyran-2 -yl)_5-((trimethylcarbinyl)ethynyl)-1Η-carbazole

Five vacuum/nitrogen cycles were used for 5_bromoindolyl-丨_(tetrahydro-2H_.pyran-2-yl)-1Η-carbazole (915 mg, 3.10 mmol; according to the procedure shown for Intermediate 1 5-bromo-4-methyl-1H-indazole prepared), cuprous iodide (72 mg, 0.38 mmol), sodium tetrachloropalladoxide (55 mg, 0.19 mm〇i), 2_(di-third A mixture of phenylphosphino)-1phenyl-1H-indole (128 mg, 0.379 mmol) and TMEDA:H 2 hydrazine (9:1, 10 mL) was degassed. Ethyltrimethylnonane' was added to the reaction and the mixture was heated at 80 ° C for 9 Torr and then cooled to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate (100 mL). The filtrate (2 X 50 mL saturated NaHC03) was washed &lt The crude material is purified on a ruthenium tube column to give the desired compound. NMR (300 MHz, DMSO-d6): δ 8.24 (s, 1 Η), 7.54 (d, 1H), 7.39 (d, 1H), 5.82 158421.doc •77-201216961 (dd,1H),3.88 (m, 1H), 3.71 (m, 1H), 2.63 (s, 3H), 2.39 (m, 1H), 2.00 (m, 2H), 1.72 (m, 1H), 1.58 (m, 2H), 0-24 (Sj 9H) ; LCMS: 313 (M+H)+ Step 2: 5-(but-1-yn-1-yl)-4-methyl-1-(tetrahydro-2H-pyran-2-yl) 1Η-°引峻

According to the procedure indicated for Intermediate 2 (Step 2) and Intermediate 3, 4-methyl-1-(tetrahydro-2H-.pyran-2-yl)-5-((trimethyldecyl) The title compound was prepared from ethynyl)-1H-carbazole. iH NMR (300 MHz, DMSCM6>. δ 7.97 (s, 1 Η), 7.27 (d, 1H), 7.11 (d, 1H), 5.59 (dd, lH), 3.58 (m, 1H), 3.50 (m, ih) ), 2.38 (s, 3H), 2.17 (q, 2H), 2.13 (m' 1H), 1.77 (m, 2H), 1.50 (m, 1H), 1.36 (m, 2H), 0.98 (t, 3H) 〇' The intermediates of Table 3 were prepared from 5-bromo-6-methyl-1H-carbazole according to the procedure indicated for Intermediate 12. Table 3·

Intermediate 13 5-( But-1-yn-1-yl)-6-methyl small (tetrahydro-2H-pyran-2-yl)_ 1 η-carbazole -------I___ THF Example 5 : Preparation of 5-(cyclopropylethynyl)β1 (tetrahydro-2H•pyran-2-yl)_1H-carbazole (intermediate 14) was cleaved into a 1 L three-necked round bottom flask. -(tetrahydro-2H-«bi-2-yl)- 158421.doc •78· 201216961 1H-carbazole (31.2 g '111 mm〇1; intermediate oxime and triethylamine (5 〇〇 rainbow). The flask was degassed using three vacuum/Ν2 cycles, followed by the addition of Pd(PPh3)2Cl2 (7.7 g, u mm〇1) and CuI (21 g, ^) under a helium atmosphere.

Mm). The flask was again degassed using two vacuum/N2 cycles. Then ethynylcyclopropane (7 〇0/〇, stored in toluene, ru, 222 mmol) was added via a syringe and the reaction mixture was stirred at 8 ° C for 16 hours. After completion, the solvent was evaporated. The residue was diluted with dioxane (6 mL), washed with water (2×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and condensed in vacuo. The residue was further purified to give the title compound (jjjjjjjjjjjjjjjjjjjj 8.09 (s, 1H), 7.82 (s, 1H), 7.70 (d, 1H), 7.39 (m, 1H), 5.84 (dd, 1H), 3.91-3.87 (m, 1H), 3.78-3.73 (m, 1H), 2.52-2.37 (m, 1H), 2.05-1.94 (m, 2H), 1.76-1.72 (m, 1H), 1.60-1.52 (m, 3H), 0.92-0.87 (m, 2H), 0.78- 0.73 (m, 2H); LCMS: 267 (M+H)+. Example 6. 5-(4-methylpent-i-block _i_yl) (tetrahydro-2-pyran-2-yl)- Preparation of 1H-carbazole (ten-body 15)

Under the A atmosphere, to the bromine in the triethylamine (3 〇mL) - (tetrahydro-2H-indol-2-yl)-1 Η-carbazole (3·〇g, 10.7 mm〇i Add 4-methylpentane alkyne (2 23 g, 27 8 mmol) to a mixture of intermediate 1), Pd(PPh3)2Cl2 (1.03 g, ΐ·〇 7 mmol) and Cul (203 mg, 1.07 mmol) . The resulting mixture was stirred at 80 ° C & N 2 atmosphere for 16 hours. After completion, the reaction mixture was diluted with EtOAc (EtOAc) EtOAc (EtOAc). The mash was washed with water (3 χ 1 mL) and dried by NaiSO 4 and concentrated in vacuo. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut elut ^ NMR (400 MHz DMSO-d6): δ 8.09 (s, 1H), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.90-3.86 ( m, 1H), 3.77-3.73 (m 1H), 2.42 - 2.32 (m, 1H), 2.33 (d, 2H), 2.05-1.94 (m, 2H), 1.86 (m, 1H), 1.76-1.71 (m , 1H), 1.60-1.54 (m, 2H), l. 〇 2 (d, 6H); LCMS: 283 (M+H)+. Example 7: Preparation of 3-(1-(tetrahydro-2H-pyran-2-yl)-iH-indazol-5-yl)propan-2-yne-1-ol (Intermediate 16)

A 500 mL 3-neck round bottom flask was charged with bromine]·(tetrahydro-2H_pyran-2-yl)-1Η-carbazole (14.0 g, 50 mmol; intermediate oxime and triethylamine (3〇〇niL) The flask was degassed using 3 vacuum/N2 cycles, followed by the addition of Pd(PPh3)2Cl2 (3.5 g, 5 mmol) and Cul (0.95 g, 5 mmol) under a atmosphere. Three vacuum/N2 cycles were used. The flask was again degassed. Prop-2-yne-g, 15 〇 mm 〇 1) was added via syringe and the reaction mixture was stirred at 8 ° C for 16 hours. After completion, the solvent was evaporated. The residue was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was further purified to give the title compound ( ii g). Ihnmr(4〇〇MHz, DMS〇d6): δ 8 13 158421.doc -80· 201216961 (s, 1H), 7.90 (S, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 5.86 (dd, 1H), 5.33 (t, 1H), 4.33 (d, 2H), 3.89-3.86 (m, 1H), 3.79-3.73 (m, 1H), 2.45-2.35 (m, 1H), 2.05-1.95 (m, 2H), 1.80-1-70 (m, 1H), 1.60-1.56 (m, 2H); LCMS: 257 (M+H)+ » Example 8: 4-(1-(tetrahydro-2H-) Preparation of pyran-2-yl)-lH-indazol-5-yl)but-3-yn-1-ol (Intermediate 17)

5-Abromo-1-(tetrahydro-2H-pyran-2-yl)-1Η·»-primedazole (17.0 g, 60.7 mmol; intermediate 1), Pd(PPh3)2Cl2 (5.80) under A atmosphere To the mixture of g, 6.07 mmol), Cul (1.20 g, 6.07 mmol), and triethylamine (170 mL), butane-3-yn-1-ol (6.80 g, 97.2 mmol) was added. The resulting mixture was stirred at 80 ° C under an A atmosphere for 16 hours. After completion, the reaction mixture was dissolved using Et 〇Ac# and washed with water (3×50 mL). The organic layer was dried over Na 2 〇 4 and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc EtOAc 4 NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H) 7.83 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 5.84 (dd, lH), 4 9 〇 ( Br,1H),3.91-3.87 (m,1H),3.77-3.70 (m,1H),3.60 (t,2H) 2.56 (t,2H),2.48-2.33 (m,1H),2.04-1.94 (m , 2H), I·%] 69 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 271 (M+H)+. Example 9: Preparation of 5-week-4-fluoro-1-(tetrahydro-2H-0 than fluoren-2-yl) oxime (middle 18) Step 1: 4-bromo-3-fluoro-2- Methyl aniline 158421.doc •81 _ 201216961

Add nbS (31·3 g, 〇.176 mol) to a solution of 3-fluoro-2-mercaptoaniline (20 g, 0.16 m〇l) in CH3CN (500 mL) at 10 °C. . The resulting mixture was stirred at room temperature for 3 minutes. Saturated Na2S2〇3 (500 mL) was slowly added to the reaction mixture at 1 °C. The organic layer was separated and the aqueous layer was extracted with ffiEt. The combined organic layers were dried over Na 2 s 4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAcjjjjj 1H NMR (300 MHz, DMSO-d6): δ 7.08 (t, 1 Η), 6.40 (dd, 1 Η), 5.35 (bi·, 2 Η), 1.98 (d, 3 Η). Step 2: 5-Bromo-4-fluorocarbazole

Add NaN〇2 (81 g, 118 mmol) to a solution of 4-Dy-3 gas-2-methylaniline (20 g, 98.0 mmol) in ch3C02 (600 mL). . The resulting mixture was stirred at room temperature for 4 hours. After completion, an aqueous NaOH solution (50%) was added to the reaction mixture until the pH was about 7-8. The mixture was extracted with EtOAc. The organic layer was dried over Najh and concentrated in vacuo. By column chromatography in silica gel (after storage in petroleum ether to 4%

The residue was purified with EtOAcqqqqqqq Nmr (300 MHz, DMS〇-d6): δ 13.58 (br, 1Η), 8.22 (s, 1H), 7.53 (t, 1H), 7.38 (d, 1H). Step 3 ··· 5-Bromo-4-fluoro-i_(tetrahydropyran-2-yl)-m-carbazole 158421.doc -82- 201216961

To a mixture of 5 bromine-lH-η azole (50 g, 0.23 mol) and DHP (23 g, 0.28 mol) in anhydrous dioxane (1 mL) at room temperature Add PTSA (2.2 g, 11.5 mmol). The resulting mixture was stirred at this temperature overnight. Upon completion, a saturated aqueous solution of NaHc(R) (100 mL) was slowly added to the mixture. The organic layer was separated, dried over Na 2 EtOAc and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)咕NMR (300 MHz, DMSO_d6 > δ 8.28 (s, 1H), 7.58-7.66 (m, 2H), 5.89 (dd, 1H), 3.90-3.85 (m, 1H), 3.79-3.70 (m, 1H), 2.42-2.29 (m, 1H), 2.06-1.94 (m, 2H), 1.77-1.68 (m, 1H), 1.60-1.53 (m, 2H); LCMS: 299 (M+H), Example 10: 5- Preparation of (cyclopropylethynyl)-4-fluoro-1-(tetrahydro-phen-2-yl)-1H-indazole (Intermediate 19)

In a high pressure tube, 5_Bromo-4-fluoro-indole (tetrahydro-2H-pyran-2-yl)-1 oxime-carbazole (8.0 g '26.8 mmol; intermediate) was used in three vacuum/nitrogen cycles. 18) Deoxygenation of a mixture of PdCl2(PPh3)2 (3.7 g, 5.35 mm〇i), cui (ι·〇g, 5.35 mmol), and triethylamine (30 mL). Ethylcyclopropane (8·9 g, 134 mmol) was added under an atmosphere of n2. The tube was sealed and the reaction mixture was heated at 120 °C for 63 hours. After completion, the mixture was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo and purified title purified elut elut elut elut elut elut elut elut eluting D6): δ 8.25 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H), 3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m, 1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m , 2H); LCMS: 285 (M+H) + </ RTI> The intermediates in Table 4 were prepared from Intermediate i according to the procedures indicated for Intermediates 14-17 and 19 . Table 4.

Intermediate 20 5-(Cyclopentylethynyl)-1-(tetrahydro-2H-»pyran-2-yl)-1Η·carbazole THP 5-(cyclohexylethynyl)-1-(tetrahydro- 2Η-° ratio j〇 intermediate 21 喃-2-yl)-1 Η-carbazole oxime intermediate 22 5-(3-methylbut-1- fast-1-yl)-1-(four wind-2Η - pyran-2-yl)-1Η-carbazole THP intermediate 23 5-(hex-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1Η-吲Azole intermediate 24 5-(3-cyclopentylprop-1-yn-1-yl) small (tetrahydro-2H-pyran-2-yl)-1 oxime-carbazole THP Example 11: 5-(4- Preparation of gas butane-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H_ 丨 丨 (Intermediate 25) 158421.doc • 84· 201216961

Under the N2 atmosphere, the water remained in the water. Add p〇ci3 dropwise to a solution of 4_(Bu(tetrahydro 2HH2-yl)_1H+)-buty-3 acetylene small alcohol (ι 〇m mm〇1; intermediate 17) (24 ^ mmol). The resulting solution was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated in the air. The residue was poured into ice-water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine, dried over Na.sub.4 and concentrated in vacuo. The residue was further purified to give the title compound (400 mg). iH NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.86 (s, 1 Η), 7.72 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 3.90-3.86 (m, 1H), 3.81 (t, 2H), 3.77-3.70 (m, 1H), 2.93 (t, 2H), 2.41-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.75-1.71 (m, lH), 1.60-1.55 (m, 2H); LCMS: 289 (M+H)+. Example 12: Preparation steps of 5-(3,3-difluoroprop-1-yn-1-yl)_1-(tetrahydro-21!-pyran-2-yl)-1 oxime-indazole (Intermediate 26) 1 : 3-(1-(tetrahydro-2H-pyran-2-yl)-1Η-indazol-5-yl)propynal

A 500 mL 3-neck round bottom flask was charged with 3-(1-(tetrahydro-2H-pyran-2-yl)-1Η-indazol-5-yl)prop-2-yn-1-ol (11.4 g) 44.2 mmol; intermediate 16), di-methane (3 〇〇 mL) and Mn 〇 2 (38.4 g, 442 mmol). The resulting mixture was stirred at room temperature for 16 hours. After completion, the filtration reaction was mixed 158421.doc -85 · 201216961. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. EtOAc m. 6.4 g). NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.27-8.25 (m, 2H), 7.87 (d, 1H), 7.66 (dd, 1H), 5.86 (dd, 1H), 3.91- 3.87 (m, 1H), 3.79-3.72 (m, 1H), 2.40-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.78- 1.72 (m, 1H), 1.61-1.56 (m, 2H) LCMS: 255 (M+H) + 〇 Step 2: 5-(3,3-Difluoroprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl) -1H-0 bow | Jun

7HP In a N2 atmosphere, fill a 500 mL round bottom flask with anhydrous two gas

(200 mL), diethylamine-3HF (8.06 g, 50.1 mmol) and XtalFluor-E (8_61 g, 37.6 mmol). The resulting solution was stirred at room temperature for 1 minute. Add 3-(1-(tetrahydro-2H-°pyran-2-yl)-1Η-oxime-5-yl)propyne (3.21 g, 12.5 mmol)' and stir the mixture at room temperature 1 hour. Upon completion, saturated NaHC〇3 (1 〇〇 mL) was added to the mixture. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over &lt;RTI ID=0.0&gt; The residue was purified by EtOAc EtOAcjjjjjjj NMR (400 MHz, DMSO-d6): δ 8.20 (s, ιΗ) 8.14 (s, 1 Η), 7.83 (d, 1 Η), 7.58 (dd, 1 Η), 6·99 (t, 1 Η), 5 9 〇 (dd, 1H), 3.90-3.87 (m, 1H), 3.79-3.73 (m, 1H), 2.45-2 37 (m, 1H), 2.05-1.96 (m, 2H), 1.79-1.65 (m, ih ), 1.60-1.56 158421.doc -86- 201216961 (m, 2H) ; LCMS: 277 (M+H)+. Example 13: Preparation of but-1-en-1-yl)-1-(tetrahydro-2Η-»biam-2-yl)-lH- ° 丨 丨 (Intermediate 27)

4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indole-5-yl)but-3-yne-1 in anhydrous di-methane (25 mL) To the solution of the alcohol (1.0 g, 3.7 mmol; intermediate 17) was added triethylamine ghf (1·2 g, 7·4 mm〇1). Then add XtalFluor-E (1.2 g, 5.5 mmol). The resulting solution was stirred at room temperature for 30 minutes. After completion, the reaction solution was neutralized by slowly adding saturated NaHC〇3 (1 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography eluting elut elut elut elut elut elut elut elut NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1 Η), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, lH), 1.58 (m, 2H); LCMS: 273 (M+H)+. Example 14 · 1-(Tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)-1 oxime-indole (Intermediate 28 Preparation Step 1 : 5-iodo-1H-carbazole Adds NaN02 to a solution of 4-indol-2-mercaptoaniline (1.09 g, 4.68 mmol) in CH3C02H (40 mL) at 10 C ( 0.39 g, 5.65 mmol) and water (1 mL). The resulting mixture was stirred at room temperature for 6 hours. After completion 158421.doc -87- 201216961, the reaction mixture was extracted with EtOAc. The combined organic layers were dried over NazS 4 and concentrated in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut 4 NMR (DMSO-d6, 400 MHz): δ 13.23 (br, 1H) 8.18 (s, 1H), 8.02 (s, 1H), 7.57 (d, 1H), 7.41 (d, 1H). Step Zen 2. 5 - Block-1-(tetrazo-211-113⁄4 鸣·2 - base bow 丨 sniffing

TMI^ is introduced into the 5-cob-1Η-» in anhydrous di-methane (20 mL) at room temperature

PTSA (0.08 g, 0.41 mmol) was added to a mixture of azole (0-90 g, 3.69 mmol) and DHP (1.57 g, 18.7 mmol). The resulting mixture was stirred overnight. Upon completion, a saturated aqueous solution of NaHC〇3 (3 〇 mL) was slowly added to the reaction mixture. The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc EtOAc 1ρί NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 8.08 (s, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 5.85 (dd, 1H), 3.88-3.85 (m, 1H), 3.78-3.72 (m, 1H), 2.41-2.29 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.72 (m, 1H), 1.61-1.56 (m, 2H) . Step 3: 1-(tetrahydro-2H-pyran-2-yl)_5·(3,3,3-trifluoropropynyl)-1Η-carbazole

N THI^ was added dropwise at -78 ° C to a solution of LDA (2 Μ, stored 158421.doc -88-201216961 in THF '3.2 mL, 6.4 mmol) in anhydrous THF (10 mL). 2. Bromo-3,3,3-trifluoropropanthene-ene (0.55 g, 3.1 mmol). The resulting mixture was stirred at this temperature for 15 minutes, followed by the addition of ZnCl 2 (1 Μ in EtOAc, 6.5 mL 6.5 mmol) and TMEDA (1 mL, 6.5 mmol). The mixture was further stirred at -78 ° C for 30 minutes and then stirred at room temperature for 3 minutes. 5-峨-1-(tetrahydro-2H-°pyran-2-yl)-1Η-β 嗤 (0.99 g, 3.0 mmol) and Pd(PPh3) 4 (0.21 g, 0·18 mmol) were added. The reaction mixture was heated at 80 ° C under an A atmosphere for 6 hours. After completion, the reaction mixture was quenched with water (1 mL) and then diluted with ethyl acetate (3 mL). The organic layer was separated, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by chromatography eluting elut elut elut elut elut elut elut elut NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.24 (s, 1H), 7.87 (d, 1H), 7.68 (dd, 1H), 5.91 (dd, 1H), 3.90- 3.86 (m, 1H), 3.79-3.72 (m, 1H), 2.41-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.76-1.72 (m, 1H), 1.60-1.56 (m, 2H) LCMS: 295 (M+H)+. Example 15: S-(4_Gas-1-yne-1-yl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1 oxime-indazole (Intermediate 29) Preparation step 1: 4-(4-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-iH-indazol-5-yl)but-3-en-1-ol

Under the A atmosphere, 5_bromo-4-pyrene is small (tetrahydro-2-indolyl-2-yl)_1H. Sit (2.80 g ' 9.36 mmol ' Intermediate 18), Pd(PPh3)2Cl2 (660 mg, 158421.doc •89-201216961 0·94 mmol), Cul (180 mg, 0.94 mmol), and triethylamine (5 To the mixture of 〇mL) was added but-3-yn-1-ol (2.0 g, 28.1 mmol). The resulting mixture was stirred at 60 ° C for 16 hours. After completion, the reaction mixture was diluted with EtOAc and washed with water (3×10 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) ), 7.64 (d, 1H), 7.49 (dd, 1H), 5.94 (dd, 1H), 4.99 (t, 1H), 3.98-3.92 (m, 1H), 3.85-3.77 (m, 1H), 3.68 ( t, 2H), 2.67 (t, 2H), 2.48-2.35 (m, 1H), 2.12-2.02 (m, 2H), 1.84-1.78 (m, lH), 1.68 -1.62 (m, 2H). Step 2: 5-(4-Actyl-1-yn-1-yl)·4_fluoro_ι·(tetrahydro-2H-pyran-2-yl)_ 1Η-«»

To exist. 4-(4-Fluoro-1-(tetrahydro-2-indole-pyran-2-yl)-1H-indazol-5-yl)butan-3-yne-1-alcohol in pyridine (50 mL) POCl3 (10.3 g, 67.3 mmol) was added to a mixture of 4.6 g, 16.0 mmol). The resulting solution was stirred at room temperature for 2 hours. After completion, the reaction solution was poured into water (25 mL) and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified to give title compound (2 62 g). iH NMR (300 MHz, DMSO-d6): δ 8·13 (s, 1 Η), 7.58 (d, 1H), 7.43 (dd, 1H), 5.87 (dd, 1H), 3-90-3.69 (m, 2H), 3.83 (t, 2H), 2.98 (t, 1H), 2.41-2.29 (m5 158421.doc 201216961 1H), 2.06-1.94 (m, 2H), 1.78-1.70 (m, lH)s 1.60-1.54 (m, 2H) ; LCMS: 307 (M+H)+. Example 16 · Preparation of 4-fluoro-5-(4-fluorobut-1-yn-1-yl)-i-(tetrahydromethane-2-yl)-1 oxime-indole (intermediate oxime 30)

'(Phenylfluoro(tetrahydro-2H_ °pyran-2-yl)-1Η-indazol-5-yl)but-3-yne-1_ol in anhydrous dioxane (100 mL) (3 4 g, u 8 mmol; intermediate 29, step 1) was added triethylamine _3HF (7 6 g, 47.2 mmol). Then, XtalFluor-E (8.0 g, 34.9 mmol) was added. The resulting solution was stirred at room temperature for 30 minutes. After completion, the reaction solution was neutralized by slowly adding saturated NaHC 3 (30 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography eluting with EtOAc (EtOAc) W NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1 Η), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H), 3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, lH), 1.60 -1.52 (m, 2H); LCMS: 291 (M+H)+. Example 17: Preparation of 5-(3methoxyprop-1-yn-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1 oxime-indazole (Intermediate 31)

Add sodium hydride (60% in mineral oil, 0.42 g, 10.5 158421.doc -91·201216961 mmol) to 3-(1-(4) in THF (20 mL) at 〇 °C A solution of hydrogen-2H-anthracene-2_yl)-1 Η-丨 丨 -5-5-yl)propan-2- fluoro-1-ol (1.01 g, 3.94 mmol; intermediate 16). The mixture was stirred at 〇 ° C for 3 , minutes, and then iododecane (1.67 g, 11.8 mmol) was added. The resulting mixture was disrupted at room temperature for 16 h. The reaction mixture was poured into ice water (1 mL) andEtOAcEtOAc The combined organic layer was washed with brine (1 mL) dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: NMR (DMSO-d6, 300 MHz): δ 8.21 (s, 1 Η), 7.93 (s, 1H), 7.73 (d, 1H), 7.47-7.45 (m, 1H), 5.85-5.83 (m, 1H), 4.38 (s, 2H), 3.76-3.71 (m, 2H), 3.35 (s, 3H), 2.40-2.37 (m, 1H), 2.03-1.94 (m, 2H), 1.73-1.72 (m, 1H), 1.57-1.55 (m, 2H). LCMS: 271 (M+H) + ??? Intermediates from Table 5 were prepared from Intermediate 1 according to procedures indicated for Intermediates 16, 17, and 31. table 5.

Intermediate 32 5_(4_decyloxybut-1-yne small group) small (tetrahydro-2H-pyran-2-yl)-1 bow sitting &lt;3^ middle Zhao 33 5-(5-曱Oxypentan-1-ynyl-1-yl)-1-(tetra-argon·2Η-«Λ-2-yl)· 1 Η-σ 弓 坐 1ΉΡ Intermediate 34 5_(6-decyloxy- 1-Alkyn-1·yl) small (tetrahydro-2-indole-pyran-2-yl yiH-11 lanthanum 7HP Example 18: Preparation of butyne-1-yltrimethyldecane (Intermediate 35) 158421 .doc -92- 201216961 Fill a 3 L two-necked round bottom flask with (trimethylformamidin) propyne (116 g, 1·19 mol) and anhydrous THF (400 mLp to cool the solution to _7yc. To this solution was added dropwise butyllithium in hexane (2.5 Μ, 500 mL, 1.25 moip) and the mixture was warmed to hydrazine. 〇 kept for 1 且 and then cooled to -78 ° C. HMPA (234 g, 1.31 mol), and the mixture was stirred for 30 minutes at -78 C. To the solution was added ethyl iodide (2 g, 1 - 28 mol). The reaction mixture was warmed to room temperature and stirred overnight. After completion, the reaction mixture was washed with water (4 x 600 mL) and then brine (2 x 500 mL). The organic layer was dried over anhydrous sodium sulfate. Filtration. Distillation of hexane and THF at 75 &lt; t to 11 〇 C. Distillation of 1,4- 1 alkyne 1 - dimethyl trioxane between 125 ° C and 135 ° C to provide 91 g of a colorless liquid (61 %) β ιΗ NMR (400 MHz, DMSO-d6) δ 2.20 (q, 2Η), 1.05 (t, 3H), 0.11 (s, 9H); 13C NMR (l〇〇MHz, CDC13): δ 108.8, 83.3 , 13.7, 13.4, 0·0. Example 19: Alternative preparation of intermediate 3

N using three vacuum/nitrogen cycles to 5-bromo-1-(tetrahydro-2-indole-pyran-2-yl)-1Η-carbazole (39.6 g '0.142 mol; intermediate 1), Cs2C03 (60.0 g) , 184 mmol), Cul (1.35 g, 7.08 mmol), Pd(OAc) 2 (1.59 g, 7.08 mmol), dppf (3.93 g, 7.08 mmol), and DMA (160 mL) were degassed. Add but-1-yn-1-yltridecyldecane (23.2 g, 184 mmol; intermediate 35), and the mixture was heated at 8 (TC and N2 for 5 h. 158421.doc -93 - 201216961 Complete LCMS The reaction mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc) The organic layer was dried over NazSCU, filtered and concentrated. EtOAc/ petroleum St (1 L petroleum ether; then 1 L EtOAc/oil) was used on a hydrazine column (300-400 mesh, 20 cm in diameter and 15 cm in height) </ RTI> = 1 / 50; and then EtOAc / pet ether = 1 / 30 until the elution of the by-products; then EtOAc / petroleum ether = 1/10 to afford product. The yellow oil solidified over time in a 4° C. refrigerator. The title compound (26 g, EtOAc) Example 20: 5-(but-1-yn-1-yl)-4-fluoro-1-(tetrahydro-2H.pyran-2-yl)-1 oxime-indole (intermediate oxime) 36) Preparation

Nitrogen was bubbled through 5-bromo-4-fluoro-1-(tetrahydro-2-indole-pyran-2-yl)-1 oxime-carbazole (19.7 g, 65.9 mmol; intermediate 18) and DMA (60 mL) ) in the solution. After 5 min, sequentially add Cul (1.25 g, 6.6 mmol), Pd(OAc) 2 (1.48 g, 6.6 mmol), dppf (3.66 g, 6.6 mmol), Cs2C03 (34.3 g, 105.4) under continuous N2 bubbling. Methyl), and but-1-yn-1-yltrimethylnonane (11.6 g '92.3 mmol; intermediate 35). The resulting mixture was heated at 80 ° C for 18 h under N2. The reaction mixture was diluted with EtOAc (900 mL) and H20 (500 mL) and then filtered. The organic layer of the filtrate was separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layer was washed with EtOAc EtOAc m. NMR (DMSO-d6, 400 ΜΗζ)·· δ 8.26 (s, 1H), 7.57 (d, 1H), 7.42 (dd, 1H), 5.87 (dd, 1H), 3.90-3-86 (m, 1H) , 3.78-3.71 (m, 1H), 2.48 (q, 2H), 2.40-2.30 (m, 1H), 2.05-1.95 (m, 2H), 1.77-1.71 (m, 1H), 1.59-1.57 O, 2H ), 1.19 (t, 3H); LCMS: 273 (M+H)+. Example 21. Preparation of 5-(Bu-1-la-l-yl)-4-chloro-1-(tetrahydro-2H-0 abi-2-yl)-1H-indazole (Intermediate 37) 1 : 4-bromo-3-gas-2-methylaniline

NBS (45.2 g, 0.254 mol) was added portionwise to a solution of 3-chloro-2-mercaptoaniline (3〇g, 0.212 m〇l) in CH3CN (300 mL) at 10 °C . The resulting mixture was stirred at room temperature for 3 minutes. Upon completion, saturate]^2^^ (5〇〇 mL) was slowly added to the reaction mixture at l〇C. The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was washed with EtOAc (EtOAc)EtOAc. 1H NMR (300 MHz, CDC13): δ 7.24 (d, 1 Η), 6.48 (d, 1 Η), 3.70 (br, 2 Η), 2.28 (s, 3 Η). Step 2: 5-Bromide·1H_carbazole

158421.doc -95- 201216961 Add to Η20 in a solution of 4-bromo-3-gas-2-methylaniline (11 g, 49.9 mmol) in CH3C02H (450 mL) at 10 °C NaN02 (5.4 g, 78.3 mmol) in (15 mL). The resulting mixture was allowed to stand at room temperature for 30 minutes. After completion, the reaction mixture was diluted with EtOAc (500 mL) andEtOAc. The organic layer was dried by NaJO4 and concentrated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 8.15 (s, 1H), 7.62 (d, 1H), 7.52 (d, 1H) 〇 Step 3. 5 - Moist 4 - Gas - 1-(tetrazo- 2H-B is more than -2 -yl)-lH-°

To a mixture of 5-di-4-ox-1H-carbazole (8.0 g, 34.6 mmol) and DHP (8.72 g, 0.104 mol) in anhydrous methane (200 mL) at room temperature Add PTS A (0.65 7 g, 3.46 mmol). The resulting mixture was stirred overnight at room temperature. After completion, a saturated aqueous solution of NaHCO (1 mL) was slowly added to the mixture. The organic layer was separated by drying and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc EtOAc 4 NMR (300 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.71 (m, 2H), 5.88 (dd, 1H), 3.89-3.84 (m, 1H), 3.79-3.73 (m, 1H) , 2.42-2.32 (m,1H),2.05-1.95 (m,2H),1.75-1.70 (m,1H), 1.60-1.54 (m,2H) » Step 4 · 5-(丁-1-快-1 -基)-4-气-1·(tetrahydro-2Η-*Λ -2--2-yl)_ih_carbazole 158421.doc -96- 201216961

Nitrogen was bubbled through triethylamine (6 mL) in a 20 mL microwave tube for 10 min. 5-Bromo-4-indol-1-(tetrahydro-2H-pyran-2-yl)-1 oxime oxazole (2.00 g, 6.34 mm 〇l) and tetrabutylammonium fluoride were added under a nitrogen atmosphere ( 3.70 g, 14.3 mmol), Cul (0.24 g, 1.3 mmol) and Pd(PPh3)4 (1.46 g, 1.26 mmol) ' and continue nitrogen bubbling for 5 minutes. Then, butyl-propyne-trimethyl decane (1.80 g, 14.3 mmol; intermediate 35) was added and the tube was immediately sealed. The reaction mixture was heated in a microwave reactor at 12 ° C for 3 hours. Combine 4 of these reactions (4 x 2 g scale / test), mix with water (1 mL), and use ethyl acetate (2 x 100 mL) )extraction. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) Compound. The solid was collected and dried to give a pale yellow powder (3.5 g). This powder was recrystallized from ethyl acetate (2 mL) to afford purified title compound (3.0 g). 4 NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.72 (d, 1H), 7.49 (d, 1H), 5.88 (dd, 1H), 3.89-3.85 (m, 1H), 3.79 -3.73 (m, 1H), 2.50 (q, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.75-1.70 (m, 1H), 1.60-1.55 (m, 2H) , 1.21 (t, 3H); LCMS: 289 (M+H) + 〇 Example 22: 5-(but-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran- Preparation of 2-yl)-1H-carbazole (Intermediate 38) Step 1: 5-Bromo-2,3-difluorobenzaldehyde 158421.doc -97- 201216961

Stored in ΗΑ04 (150 mL) in three portions at 60 ° C for 30 minutes.

Add nbS (63 g, 0.354 mol) to a solution of 2,3-di-benzoic acid^ (42 g, 0,296 mol). The resulting mixture was heated at this temperature and n2 for 6 hours. Treatment: The reaction mixture was poured into ice water. A petroleum puzzle (3 〇〇 mL) was added and the mixture was stirred for 1 Torr. The organic layer was separated and the aqueous layer was extracted again using petroleum ether (300 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography eluting EtOAc (EtOAc:EtOAc) iH NMR (300 MHz, CDC13)·· δ 10.32 (s, 1H), 7.81-7.79 (m, 1 Η), 7.65-7.60 (m, 1 Η). Step 2: (E)-5-Moly-2,3-difluorobenzaldehyde 〇_f 肟

5-Bromo-2,3-difluorobenzaldehyde (17.38 g, 78.6 mmol), hydrazine-hydrazinohydroxylamine hydrochloride (7 23 g, % 46, and K2C03 (13) in DME (80 mL) The mixture of g' 94_32 mmol) was at 4 Torr. (: heating for 14 h. Treatment. · Filter the reaction mixture. Concentrate the filtrate in vacuo and pass the column layer = in the gum (in petroleum ether to 2) The residue was purified to give (E)-5-bromo-2,3-difluorobenzaldehyde oxime-methyl hydrazide (19 65 g). lH nmr (CDC13, 300 MHz): δ 8.20 ( s, 1H), 7.76-7.73 (m, 1H), 7.35- 7.29 (m, 1H), 4.01 (s, 3H). Step 3: 5-bromo-7-fluoro-in-carbazole 158421.doc -98 - 201216961

a mixture of (E)-5-bromo-2,3-difluorophenylvaleraldoxime-methylhydrazine (19 65 g, 78 6 mmol), hydrazine hydrate (8 mL), and anhydrous raF (80 mL) Heating at 90 ° C for 84 he treatment: evaporation of the organic solvent. The resulting mixture was diluted with EtOAc (4 (9) mL), washed with water (150 mL), dried Na? The residue was purified by column chromatography eluting with EtOAc (EtOAc (EtOAc) ). iH NMR (300 MHz, CDC13): δ 13.83 (br, 1H), 8.16 (s, 1H), 7.78 (s, 1H), 7.45 (d, 1H). Step 4: 5-Bromo-7-fluoro_i_(tetrahydro-2H-pyran-2-yl)-1Η-carbazole

5_Bromo-7-IL-1H-吲 saliva (9.3 g, 43.26 mmol) and DHP (4.36 g, 51.9 mmol) in anhydrous di-methane (1 mL) at room temperature PTS A (424 mg, 2.16 mmol) was added to the compound. The resulting mixture was stirred overnight. Treatment: NaHC〇3 saturated aqueous solution (30 mL) was slowly added to the mixture. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on EtOAc (EtOAc EtOAc EtOAc EtOAc) 0 South-2-base) -1Η-0 induces saliva (7.8 g). ^ NMR (300 MHz, CDC13): δ 7.98 (s, 1H), 7.64 (s, 1H), 7.22 (dd, 1H), 5.84 (dd, 1H), 4.07-4.02 (m, 1H), 3.78-3.71 (m, 1H), 2.62-2.53 (m, 1H), 2.16-2.07 (m, 2H), 1.79-1.71 (m, 2H), 1.63-1·33 (m, 1H). 158421.doc •99- 201216961 Step 5: 5-(but-1-yn-1-yl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1Η-吲 sniff

Nitrogen was bubbled through a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-l-indazole (7.5 g, 25.33 mmol) and DMA (100 mL). After 5 min, Cul (241 mg, 1.27 mmol), Pd(OAc) 2 (284 mg, 1.27 mmol), dppf (704 mg, 1.27 mmol), K2C03 (4.89 g) were added sequentially under continuous N2 bubbling. , 35.46 mmol), and but-1-yn-1-yltrimethylnonane (4.46 g, 35.46 mmol). The resulting mixture was heated at 80 ° C for 10 h under n2. The reaction mixture was diluted with EtOAc (250 mL) and H20 (200 mL) and filtered. The organic layer of the filtrate was separated and the aqueous layer was extracted with Et.sub.2 (2×100 mL). The combined organic layers were washed with brine (3×5 mL), dried over anhydrous Na.sub.sub. 3 6 g) and impure product (2 g; further purification to give i 47 g additionally). lH NMR (3〇〇MHZ, DMS〇-d6): δ 8.19 (d, 1H), 7.68 (d, 1H), 7.26 (dd, 1H), 5.79 (dd, 1H), 3.92-3.87 (m, 1H) ), 3.69-3.60 (m, 1H), 2.47-2.34 (m, 1H), 2.43 (q, 2H), 2.07-2.02 (m, 2H), 1.76- 1.69 (m, 1H), 1.57-1.50 (m , 2H), 1.17 (t, 3H) ; LCMS: 273 (M+H)+. Example 23: Preparation of 5-bromo-3-fluoro-1-(tetrahydro-2H-tono-2-yl)-ih-carbazole (Intermediate 39) Step 1: 5-bromo-3-fluoro- In-carbazole 158421.doc 201216961

5-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1 oxime-carbazole (10.0 g, 35.7 mmol; intermediate 1), acetic acid (4 mL), selective fluor. A mixture of (25.3 g, 71.4 mmol) and acetonitrile (1 mL) was refluxed for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (42 mL) and then washed with water (270 mL). The organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc 4 NMR (DMSO-d6, 400 MHz): δ 12.77 (s, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H) 〇 Step 2: 5-bromo-3-fluoro -1-(tetrahydro-2H-&quot;pyran-2-yl

5-Bromo-3-fluoro-1H-indazole (6.0 g, 27.9 mmol), PTSA (530.7 mg, 2.79 mmol) and DHP (3.05 g 36_3 mmol) in dichloromethane (8 mL) The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with di-methane (370 mL) and washed with water (23 mL). The organic layer was dried over NasSO4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc NMR_(DMSO-d6, 400 MHz): δ 7.96 (s, 1H), 7.70 (d, 1H), 7.60 (d, 1H) 5.76 (dd, 1H), 3.84-3.80 (m, 1H), 3.71-3.64 (m, 1H), 2.20-2.15 (m 1H), 1.97-1.87 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.47 (m, 2H)). 158421.doc -101 - 201216961 Example 24: 5·(丁-1-yn-1-yl)-3_fluoro(tetrahydro-2Hpyran-2-yl)·1H-indazole (intermediate 4〇) Preparation

Packing 5_bromo^-fluoroantimony (tetrahydro-2H-pyridyl) sequentially into a 100 mL round flask

喃-2-yl)-1Η-'^ (6.2 g' 20.7 mmol; intermediate 39), DMA (20 mL), Cul (393.3 mg, 2.07 mmol), Pd(OAe)2 (465.0 mg, 2.07 mmol) 'dppf (1.1 g5 2.〇7 mmol) ^ Cs2C03 (10.8 g, 33.1 mmol), and but-1-yn-1-yltridecyldecane (3 4 g, 26 9 mmol; intermediate 35) The cockroach is bubbled through the solution. The resulting mixture was heated at 80 ° C for 10 h under N2. The reaction mixture was diluted with EtOAc (350 mL) and H.sub.2 (300 mL) and filtered. The organic layer of the filtrate was separated and aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL) dried over anhydrous Na. The title compound (3.9 g, yield: 69.1%) was obtained eluted elute 4 NMR (DMSO-d6, 400 ΜΗζ): δ 7.76-7.71 (m, 2H), 7.49 (d, 1H), 5.79 (dd, 1H), 3.88-3.85 (m, 1H), 3.74-3.71 (m, 1H), 2.44 (q, 2H), 2.24-2.21 (m, 1H), 2.01-1.91 (m, 2H), 1.70-1.65 (m, 1H), 1.57-1.54 (m, 2H), 1.18 (t, 3H) ; LCMS: 273 (M+H)+. Example 25: Preparation of 5-(3-cyclopropylprop-1-yn-i-yl)_i_(tetrahydro-2H-pyran-2-yl)-1 oxime-indazole (Intermediate 41) Step 1: (3-cyclopropylprop-1-yn-1-yl)trimethyldecane 158421.doc -102· 201216961

A 500 mL 3-neck round bottom flask was charged with (trimethyldecyl)propyne g, 153 mmol) and anhydrous THF (75 mL). The solution was cooled to _78t &lt;c&gt;, and a solution of n-butyllithium in hexanes was added dropwise 5 min, 75 mL, 188 mmol) over 30 min. The resulting mixture was stirred for 1 minute and then cooled to -78 °C. HMPA (40 g, 223 mmol) was added and the mixture was stirred at -78 °C for 30 min. Then (bromomethyl)cyclopropane (20.6 g, 153 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completion, the reaction mixture was washed sequentially with water (4 x 100 mL) and brine (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, and hexane and THF were distilled at 75 ° C to 110 ° C and then at 138. (: to 142. (: Distilled to give the title compound (12 g). NMR (400 MHz, DMSO-d6): δ 2.27 (d, 2H)S 0.91-0.84 (m, 1H), 0.43-0.34 (m , 2H), 0.19-0.14 (m, 2H), 0.11 (s, 9H). Step 2: 5-(3-cyclopropylprop-1-yn-1-yl)-1-(tetrahydro-2H- Pyran-2-yl)·1Η-β

5 Under a Ν2 atmosphere, to 5-bromo-1-(tetrahydro-2-indole-pyran-2-yl)-1 oxime-carbazole (4.0 g, 14.3 mmol; intermediate l), Pd(PPh3)2Cl2 (1.0 g, 1.43 mmol) 'Cul (271 mg, 1.43 mmol) ' TBAF (11.2 g, 42.8 mmol), triethylamine (20 mL), and THF (20 mL) 1-Alkyn-1-yl)trimethyldecane (7.9 g, 42.8 mmol). The resulting mixture was stirred at 8 (TC and N2 atmosphere for 16 hours. After completion) using 158421.doc • 103· 201216961

The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water (3 χ 1 mL), dried over NaeEtOAc and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc NMR (400 MHz, DMSO-d6): δ 8.09 (S, 1 Η), 7.84 (s, 1H), 7.69 (d, 1H), 7.39 (dd, 1H), 5.83 (dd, 1H), 3.89-3.86 ( m, 1H), 3.77-3.70 (m, 1H), 2.49 (d, 2H), 2.43-2.34 (m, 1H), 2.05-1.94 (m, 2H), 1.79-1.71 (m, 1H), 1.60- 1.55 (m, 2H), 1.06-0.96 (m, 1H), 0.52-0.46 (m, 2H), 0.30-0.25 (m, 2H); LCMS: 281 (M+H)+. Example 26: Preparation of (cyclobutylethynyl)trimethyldecane (Intermediate 42) Step 1: (6-Gas-1-yne-yl)-trimethyldecane

Add n-butyllithium (2.5 Torr) to a solution of 6-chlorohex-1-yne (100 mL, 94.6 g, 0.82 mol) in anhydrous Et20 (500 mL) over 40 min. , stored in hexane, 360 mL, 0.90 mol). The resulting mixture was stirred at -78 °C for 30 minutes. Then gas tridecyl decane (125 mL, 1.0 mol) was added. The mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was carefully quenched with a saturated aqueous solution of NEUC1 (300 mL) and extracted with Et.sub.2 (2×200 mL). The combined organic layers were washed with brine (2 mL EtOAc) 4 NMR (DMSO-d6, 400 MHz): δ 3.65 (t, 2H), 2.25 (t, 2H), 1.82-1.75 (m, 2H), 1.58-1.51 (m, 2H), 0.12 (s, 9H) . 158421.doc -104· 201216961 Step 2: (cyclobutylethynyl)trimethylnonane

Add n-butyl group (2·5 μ, stored in hexane) dropwise to a bath of diisopropylamine (153 g, 1.52 mol) in anhydrous THF (1.0 L) at 〇 °C. 608 mL, 1.52 mol). The mixture was placed in a crucible. The mixture was stirred for 2 minutes and then cooled to -78 °C. To the mixture was added dropwise a solution of (6-chlorohex-1-yn-1-yl)trimethylsulfanyl (144 g, 0.76 mol) in anhydrous thf (200 mL). The resulting mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was carefully quenched with a saturated aqueous solution of ΝΗβΙ (500 mL) at room temperature and then extracted with pentane (2×2 〇0 mL). The combined organic layers were washed with brine (500 mL:) and dried over anhydrous Naj. The solvent was evaporated on a rotary evaporator. The residue was evaporated to give the title compound (yield: 70%). NMR_ (CDC13,400 MHz): δ 3.05-3.01 (m,1H), 2.26-2.20 (m,2H) 2.17-2.10 (m,2H),1.93-1.84 (m,2H),0.11 (s,9H) . Example 27: Preparation of 5-(cyclobutylethynyl)-1-(tetrahydro-2H-pyran-2-yl)·ΐΗ-«· oxazole (Intermediate 43)

A 5-mL round-bottomed flask was charged with 5-bromo-1-(tetrahydro-2-indole-pyran-2-yl)-1 oxime-carbazole (6.8 g, 24.2 mmol; intermediate 1), DMA (30 mL). , Cul (0.46 g, 2.4 mmol), Pd(OAc) 2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2C〇3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl) Trimethyl decane (5.2 g, 34.1 mmol; 158421. doc - 105 - 201216961 Intermediate 4 2 ) while bubbling N 2 through the mixture. The resulting mixture was heated at 80 ° C under an A atmosphere for 2 hours. The reaction mixture was cooled to room rt and diluted with EtOAc EtOAc (EtOAc) The organic layer of the filtrate was separated and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3 EtOAc EtOAc EtOAc). The residue was purified with EtOAc EtOAc EtOAc EtOAc EtOAc 4 NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75- 1.70 (m, 1H), 1.58-1.55 (m, 2H): EtOAc: EtOAc: Table 6 · Intermediate Zhao 44 5_(cyclobutyl ethynyl)_3_ defeat (tetrahydro-2H-pyridyl P, -2-yl-b-indole ΤΗ〆 general procedure A: tetrahydropyran for oxazole nh (THP) protection group loading 0

3,4-Dihydro-2H-pyran (1.1-10 equivalents) was added to the appropriate function at room temperature. Sit (1. 0 equivalents), PPTS (or pTsOH, 0.05-0.3 equivalents), and two 158421.doc 201216961 gas-burning (about 2 mL/mmol) solution. The reaction was spoiled under N2 for 6-48 h (until TLC or LCMS was completed), the reaction was quenched with water and then extracted with di-methane. The extract is dried, filtered, concentrated, and purified by EtOAc to afford purified carbazole. General Procedure B: Coupling of protected halozole with alkynyl-trimethylnonane

Use three vacuum/nitrogen cycles to properly protected functional carbazole (1. 〇 equivalent), Cs2CO3 (1.3-3.0 eq.), Cul (0.05-0.2 eq.), 卩 &lt;1 (〇八(:)2( a mixture of 0.05-0.2 equivalents, (^?£&gt; (0.05-0.2 equivalent), and ]^,:^-dimethylacetamide (DMA, 1-2 mL/mmol) is degassed. Alkynyl-tridecyldecane (1.3-2.0 eq.), and the reaction is heated at 8 (TC and 乂 under 2-24 hours (until TLC or LCMS is completed). The reaction is cooled to room temperature using ethyl acetate and It was diluted with water and then filtered through celite. The aqueous layer was separated and extracted with ethyl acetate. The organics were combined, dried, filtered and concentrated, and then purified by column chromatography to give alkynyl-carbazole. · The alternative test includes K2C〇3 and CsF; the replacement ligand contains ι,3_bis(2,4,6-trimethylphenyl) gasified imidazole rust and pj^p; the replacement catalyst contains Pd(PPh3)4 And PdClAPPh3)2; the alternative solvent comprises thf and pyrrolidine. The water content seems to affect the rate of this reaction: when using anhydrous Cs2C〇3 and anhydrous solvent, add 1% water (v/v about solvent) In the reaction, and when CsjCO3 and/or the solvent is not anhydrous, no water is added. An alternative private sequence is also used, especially the filling: the appropriate alkynyl group - triterpene base stone burning (2. ^ when 158421.doc • 107·201216961) added to the TBAF degassed solution (2.0 eq, 0.5 Μ in THF). After 5-30 min, add the appropriate carbazole (1.0 eq.), CuI (〇.05-0.3) Equivalent), and Pd(PPh3)4 (〇.〇5-0.2 equivalent). Stir the reaction at room temperature and underarm for 2-24 hours (until TLC or LCMS is completed), then dilute with water and use the appropriate solvent. The extracts are combined, dried, filtered, concentrated, and then purified by column chromatography to give the alkynyl-carbazole. Note: The replacement catalyst comprises PdCl2(PPh3)2; the cosolvent comprises triethylamine and pyrrole Pyridine; when using a bromo-heterocyclic ring, raise the reaction temperature (80-120. 一般. General procedure C: a multi-component cross-coupling of alkynyl-carbazole.

The appropriate alkynyl-carbazole (1. A mixture of methyl decylamine (DMF) / water (2:1, 50 mL / mmol) was degassed and then at 45. After heating for 10 minutes under the armpits (or when the solution is homogeneous), a solution of Pd(PhCN)2Cl2 (0.01 equivalent) in DMF was added. The reaction was stirred at 45 ° C for 4-24 h (until TLC or LCMS was completed) and cooled to room temperature. &lt;EMI ID=9.1&gt; The extract was washed with water, washed with brine, dried, filtered, concentrated, and purified by silica gel chromatography to give the desired tetra-substituted olefin. Note 1: In some cases, all chemicals are simply mixed at room temperature 158421.doc • 108 · 201216961 mixed, degassed, and then heated, DMF/water solution. In other cases, the last addition of boric acid Note 2: When an alkynyl group is called an ortho-substituted aryl iodide, $acid, and K2C03 (1-3 equivalents each time). When the sitting conversion is incomplete (especially using additional D aryl iodide, aryl boron.) and heating is continued for 8-24 h. In some cases, this process is repeated several times to improve conversion and yield. General procedure D: Alkynyl, carbazole alternative multi-component cross-coupling.

步尔1: Shuang (Huanqi) two-collar base - the formation of rare

Use three vacuum/N2 cycles for the appropriate alkynyl-carbazole (1. decyl equivalent), bis (pentane) diboron (1.01-1.02 equivalent), Pt (PPh3) 4 (0.0025-0.03 equivalent; note 1), And the solvent (2 mL / mmol dioxane, DME, 2-MeTHF, PhMe, or DMA; Note 2) solution is degassed, and then heated at 80-120 ° C (Note 3) and N2 1-8 h (until TLC or LCMS is completed). The reaction is cooled to room temperature and then 1) used directly in step 2; 2) concentrated to give a crude residue [usually a foam]; or 3) concentrated and purified by gelatin chromatography to give pure bis(pentamidine) ) two shed base-ene. Note 1: Most commonly, 0.01 equivalents are utilized. Note 2: Most commonly, 2-MeTHF is utilized. Note 3: Most commonly, the reaction is refluxed. Step 2: Cross coupling of bis(pentamethylene) diborane-ene 158421.doc •109- 201216961

Bis(pentamethylene)diboryl-ene (1.0 eq.), appropriate 4-iodoaryl-aldehyde (1.0 eq.), PdCl2 (PPh3) 2 (0.02-0.1 eq; Note 1), Cs2C03 (1_3-3) Equivalent; note 2), solvent (4 mL / mmol: dioxane, hydrazine) \ ^, 2-MeTHF, PhMe, DMA; note 3 and 4), and water (0-3% v / v; note 5) The mixture was stirred vigorously at 20-40 ° C (Note 6) and N 2 (Note 7) for 1-24 h (until TLC or LCMS was completed). The reaction solution 1) is then used directly in step 3; or 2) treatment to isolate 1-aryl '-2-(pentamidine)boryl-ene: [diluting the reaction solution with diethyl ether (or ethyl acetate) and using water (1-3 times) washing. The aqueous phase was back extracted with diethyl ether (or ethyl acetate). The extracts were combined, dried, filtered, concentrated and then purified by silica gel chromatography. Note that most commonly, 0.1 equivalents are used. The alternative catalyst contains PdCl2 (dppf). Note 2: Most commonly, 2 or 3 equivalents are used. The water content of Cs2C03 will affect this reaction, see Note 5. Note 3: Most commonly, 2-MeTHF is used. Note 4: When bis(pentamidine)diboryl-ene is introduced into this step as a bath from step 1, a solvent (2 mL/mmol) is added to prepare a final volume of solvent of about 4 mL/mmol. . Note 5: The most common use of anhydrous CsAO3 and anhydrous solvent is to add 1 _2 〇 / 〇 water (Wv for solvent) to the reaction. When ChCO3 and/or the solvent is not anhydrous, no water is added. Note 6: Most commonly, the reaction is carried out at room temperature. Note 7: In some cases, the reaction was degassed using three vacuum/n2 cycles. 158421.doc 110 201216961 Step 3: Cross-coupling of 1-aryl-2-(pentamethylene)boronyl-ene

Use 1-vacuum/N2 cycle to 1-aryl-2-(pentamidine)boryl-ene (1.0 eq.), appropriate aryl halide (1.3-2 eq.; Note 1), PdCl2 (PPh3) 2 (0.02 -0.1 equivalent; note 2), solvent (4 mL / mmol: dioxane, DME, 2-MeTHF, DMSO; note 3 and 4), and a mixture of KOH (3-6 Μ, 5-6 equivalent; note 5) Degas and then heat at 80-100 ° C (Note 6) and A for 1 - 24 h (until TLC or LCMS is completed). The reaction was cooled to room temperature, diluted with diethyl ether (or ethyl acetate) and washed with water (1 - 3). The aqueous phase was back extracted with diethyl ether (or ethyl acetate). The combined extracts were &apos;dried&apos;filtered&apos; concentrated and then purified by gel chromatography to give the desired tetrasubstituted dilute. Note 1: Most commonly, 1.5 equivalents of aryl iodide is used. Note 2: Most commonly, use 〇" equivalent. The alternative catalyst contains Pdcl2 (dppf). Note 3: Most commonly, dioxane, DME, or 2-MeTHF is used. Note 4. No additional solvent or PdCl2(PPh3)2 was added when 1-aryl-2-(pentamidine)boronyl-dilution was introduced directly from step 2 into this step. Only aryl halides and KOH are added. Note 5: Most commonly, 6 equivalents of KOH are used, and the aqueous KOH solution is 4 Torr or 6 Torr. For compounds with sensitive functional groups, K2C03 (6 equivalents, 4 Torr aqueous solution) was used instead of hydrazine, and DMSO was used as the sole solvent or cosolvent. Note 6: Most commonly, the reaction is refluxed. General procedure Ε: olefination of tetrasubstituted aryl aryl-aldehydes 158421.doc 201216961

At room temperature, we, 8-diazabicyclo [5·4〇] eleven · 7 dilute (dbu,

And a mixture of anhydrous acetonitrile (2 mL / mmol). Will think, s people this: ua .........

Filtration, concentration, and purification by gel column chromatography to give the desired acrylic acid. Note 1: In some cases, an alternative phosphonate reagent is utilized to obtain the desired acrylate. Note 2: Alternative reaction conditions: 1-2 equivalents of the phosphonate in THF are treated with n-BuLi or NaH (1-2 equivalents) at _78〇c or 〇&lt;t. The aryl-aldehyde (1 equivalent) was then added and at -78. ^, 〇. The reaction is continued at room temperature or at room temperature until the reaction is completed by TLC and/or LCMS. General Procedure F: Removal of the tetrahydropyran protecting group from carbazole.

The HCl solution (Note 1) was added to a solution of THP-protected oxazole (1. 〇 equivalent) in ethanol (2-5 mL/mmol; Note 2) at room temperature. The mixture was at 70. (: under (Note 3) heating for 2-8 h (until TLC or LCMS is completed), cooled to room temperature, and concentrated to give a crude product. The crude product 158421.doc • 112· 201216961 was used directly in the next step. Or purified by gelatin chromatography. Note 1. Most commonly, 2 M HCl in diethyl ether or 1.25 M HCl in ethanol is used. Most typically, the volume of HCl solution used is 10 of the volume of the bath. %. Note 2: Most commonly, the concentration is 5. In some cases, use decyl alcohol or isopropanol. Note 3: In some cases 'react at 8 〇. (: or under reflux. General procedure G : Hydrolysis of acrylate to acrylic acid.

Add an aqueous solution of LiOH (2-20 equivalents; note 丨) to a solution of the appropriate ester in ethanol/tetrahydrofuran (1:1, 10 mL/mm〇1; Note 2) at room temperature (1. In the equivalent), and stir the mixture for 4-24 h (until TLC or LCMS is completed). Add HCl solution (1 Μ aqueous solution) until pH is 3 (Italian 3). Dilute the mixture with water and extract with ethyl acetate (or gas or ether). Wash the organic layer with water, wash with brine, dry 'transition' concentrate and purify by gelatin chromatography or preparative HPLC to obtain the desired acrylic acid. Idea 1: Most commonly, use a 2 Μ aqueous solution of Li 〇 H, or leave LiOH in a minimum amount of water. In some cases, Na〇H or K〇H is used. Note 2. In some cases, a single solvent (ethanol, dioxane, or tetrahydrofuran) is used. Note 3: An alternative treatment procedure is used, which includes: 丨) using saturated NH4Cl instead of the aqueous solution of hci, and 丨丨) removing the organic solvent by rotary evaporation before the acid is quenched. 158421.doc -113- 201216961 Example 28: Compound 1 : (E)-3-(4-((E)_l-(lHH5-yl)phenyl)-1-phenyl-1-yl)phenyl)acrylic acid Preparation of ethyl ester Step 1: (Ε)-3-(4-((Ε)-2-phenyltetrahydro-2Η-pyran-2-yl)-1HH5-yl)butyl succinyl) Ethyl acrylate

Using 5 vacuum/Ν2 cycles for 5_(butynyl)_丨_(tetrahydro-2-indole-pyran-2-yl)-1Η-° 0 sitting (2.5 g, 9.83 mmol, intermediate 3), moth Benzene (6 g, 29.5 mmol), (E)-(4-(3-ethoxy-3-tritoxyprop-1-en-1-yl)phenyl) linonic acid (6.49 g, 29.5) A solution of mm〇i), k2C03 (4.08 g, 29.5 mmol), and N,N-dimercaptocaramine/water (2:1, 492 mL) was degassed and then heated at 45 °C until It is a homogeneous solution. A solution of Pd(PhCN)2Cl2 (38 mg, 0.098 mmol) in N,N-dimethylformamide (0.5 mL) was added. The resulting mixture was scrambled overnight at 45 °C. After completion, the reaction mixture was cooled to EtOAc EtOAc (EtOAc) The combined organics were washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to give crude. The crude material was purified to give the title compound (3.71 g). LCMS: 423 [(M-THP+H)+H]+. Step 2: (Ε)-3-(4-((Ε)-1-(1Η-&quot; 丨 _ _5_ yl)) 2 phenyl butyl succinyl) phenyl) acrylate ethyl ester • 114- 158421 .doc

201216961

(Ε)_3·(4_((Ε)_2phenyl-1-(1-(tetrahydro-2-pyran-2-yl))-1Η) in ethanol (69 mL) at room temperature Add HCl (6 mL, 2 Μ, in diethyl ether) to a solution of ethyl phenyl) acrylate (3.5 g, 6.9 mmol). The resulting mixture was then heated at 7 Torr c for 2 h. After completion, the mixture was cooled to room temperature and concentrated to give a crude material. The crude material was purified on a silica gel column eluted with EtOAc - EtOAc (EtOAc) elute iH nmr 〇(9) MHz, DMSO-d6): δ 13.10 (s, 1Η), 8.08 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.48 (d, 1H), 7.39 (d5 2H), 7.27-7.11 (m, 6 H), 6.89 (d, 2H), 6.45 (d, 1H), 4.20 (q, 2H), 2.43 (q, 2H), 1.22 (t, 3H), 0.87 ( t,3H) ; LCMS: 423 (M+H)+. Example 29 - Compound 2: (E)-3-(4-((E)-l-(lH-indazol-5-yl)-2-phenylbut-1-ylidene-1-yl)phenyl) Preparation of acrylic acid

(Ε)·3-(4- in THF-EtOH (1:1, 59 mL) at room temperature

An aqueous solution of mU〇h (2.8 g, 118 mmol; dissolved in a minimum of water) was added to a solution of the ester (2_5 g, 5.9 mmol; Compound i). The resulting mixture was stirred overnight. After the completion of the reaction by LCMS, the aqueous solution of 丨N HCi was added until the pH was 3. Then, the mixture was diluted with water and extracted with acetic acid 158421.doc 115· 201216961 ethyl acetate (3 x 200 mL). The combined organic layers were washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to give crude. The crude material was purified to give the title compound (19 g) as a pale yellow solid. H NMR (300 MHz, DMSO-d6): δ 13.11 (s, 1H), 12.30 (br, 1 Η), 8.08 (s, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.43 ( d, 1H), 7.37 (d, 2H), 7.29-7.11 (m, 6 H), 6.88 (d, 2H), 6.37 (d, 1H), 2.44 (q, 2H), 0.87 (t, 3H); LCMS: 395 (M+H)+. Compounds 3 to 89 were prepared from the alkynyl-hydrazine intermediate according to the general procedures C, F, and G. The alkynyl-carbazole intermediates have been prepared i) as described herein or (1) according to the general procedures A and B from known or commercially available halocazoles. Compounds 90 to 92 are derived from the synthesis of intermediates of compounds 3, 12, and 13. Example 3: Compound 93: (E)-3-(4_((E)-2-(3hydroxyphenyl)-1.(ιη-oxazol-5yl)but-1-ene_1_yl Preparation of phenyl)acrylic acid

Recycling to l〇-mL equipped with a magnetic stir bar, rubber septum and Ν2 inlet

The flask was filled with (Ε)-3-(4-((Ε)-1-(1Η-oxazol-5-yl)-2-(3-decyloxyphenyl)but-1-en-1-yl Phenyl)acrylic acid (3 〇 mg, 0.07 mmol, compound 5) and DCM (1.4 mL). This solution was cooled to hydrazine in an ice bath. Hey. Then BBr3 (88 mg, 0.35 mmol) was added dropwise via a syringe. The reaction mixture was stirred at 0 ° C for 1 h. After completion, the reaction was terminated using methanol (5 mL) at 0 ° C 158421.doc -116 · 201216961. The resulting mixture was concentrated under reduced pressure to give a crude product. The title compound (11 mg) was obtained as a white solid. 4 NMR (300 MHz, DMSO_d6;): δ 13.11 (s, 1 Η), 12_32 (br, 1 Η), 9.23 (s, 1 Η), 8·08 (s, 1 Η), 7.62 (s, 1H), 7.52 ( d, 1H), 7.45-7.35 (m, 3H), 7.12 (d, 1H), 7.00 (t, 1H), 6.90 (d, 2H), 6.59-6.53 (m, 3H), 6.36 (d, 1H) , 2.37 (q, 2H), 0.89 (t, 3H); LCMS: 411 (M+H)+. Example 31: Compound 94: (Ε)-3·(4-((Ε)·2-(2-Phenylphenyl)·ι_(1Η-β-丨丨-5-yl)but-1--- Preparation of 1-yl)phenyl)acrylic acid

(E)-3-(4-((E)-l-(lH-吲唾--) was placed in a 10 mL recovery flask equipped with a magnetic stir bar, a rubber septum and a Ν2 inlet in DCM (6 mL). 5-yl)-2-(2-decyloxyphenyl)butan-1-l-l-yl)phenyl)propanate B g (l45 mg ' 〇. 32 mmol, in the synthesis of compound 12 Intermediate). The solution was cooled to -78 °C in an IPA/dry ice bath. Then, BBr3 (241 mg, 0.96 mmol) was added dropwise via a syringe. The reaction mixture was gradually warmed to 〇 ° C for 1 h. After completion, use decyl alcohol (5 mL) at 0. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was then dissolved in THF-EtOH (1:1, 6 mL), and an aqueous solution of LiOH (0.15 g) was added at room temperature. The mixture was stirred at room temperature overnight at 6.4 mmoip. The reaction was monitored by LCMS. After completion, 1 N aqueous HCl solution was added 158421.doc -117 - 201216961 to pH 3. Then the mixture was diluted with water and acetic acid was used. The mixture was extracted with EtOAc (3 mL, EtOAc) (EtOAc)EtOAc. This crude material was purified using EtOAc EtOAc (EtOAc: EtOAc) δ 13.07 (s,1H), 12.34 (br, 1Η), 9.33 (br, 1H), 8.08 (d, 1H), 7.65 (s, 1H), 7.53 (d,1H), 7.40 (d,1H), 7.32 (d, 2H), 7.15 (dd, 1H), 7.00-6.94 (m, 3H), 6.81-6.76 (m, 2H), 6.57 (dt, 1H), 6.34 (d, 1H), 2.43-2.30 ( m, 2H), 0.88 (t, 3H) ; LCMS: 411 (M+H)+. Compound 95 was prepared according to the procedure for compound 94. Example 32: Compound 96: (Ε)_3·(4_((Ε)_2·(3_ Butoxyphenyl) (1Η) -»引唾-5-yl) butyl small diphenyl) phenyl) acrylic acid preparation step 1: (Ε)-3·(4-((Ε)-2-(3-hydroxyphenyl) -1-(1-(tetrahydro-211-.pyran-2-yl)-1Η-&quot;5丨 succinyl) butyl·i-di-j-phenyl)ethyl acrylate

Prepared according to the general procedure C from intermediate 3, 3-iodophenol, and (E)-(4-(3-ethoxy-3-oxacylpropan-1-en-1-yl)phenyl)boronic acid Title compound. Step 2: (Ε)-3-(4-((Ε)·2-(3-Butoxyphenyl(tetrahydro-2H-^)-2-yl)-1Η·»5丨峻-5· Ethyl)butenyl)phenyl)ethyl acrylate 158421.doc 201216961

Potassium carbonate (53 mg, 0.38 mmol) was added to (E)-3-(4-((E)-2-(3-hydroxyphenyl)_ι_(ι_(tetrahydrogen) in CH3CN (1 mL) -2H-°pyran-2-yl)-1 Η-0 丨 0 -5-5-yl) Butyr-ene-1-yl)phenyl) acetoacetate (1 〇 1 mg, 0.19 mmol) in. After 15 min of the drop, mothidine (24 pL, 0.21 mmol) was added. The reaction was stirred at room temperature for 15 h. Additional iodine butane (24 μ, 0-21 mmol) was added and the reaction was stirred at 60 ° C for 10 h and then at room temperature for 48 h. The reaction was diluted with dichloromethane and filtered through celite. The filtrate was concentrated and purified by EtOAc (EtOAc-EtOAcEtOAcEtOAc) -butoxyphenyl)-1-(1-(tetrahydro-2Η-βpyran-2-yl)-1Η-β5| °坐-5-yl)but-1-enrichment·ι_yl)phenyl Ethyl acrylate. 4 NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1 Η), 7.73 (d, 1 Η), 7.64 (s, 1 Η), 7.49 (d, 1 Η), 7.41 (d, 2H), 7.24 (dd , 1H), 7.12 (t, 1H), 6.91 (d, 2H), 6.76 (d, 1H), 6.67-6.72 (m, 2H), 6.48 (d, 1H), 5.86 (d, 1H), 4.15 ( q, 2H), 3.86-3.94 (m, 1H), 3.72-3.80 (m, 3H), 2.38-2.46 (m, 3H), 1.96-2.10 (m, 2H), 1.70-1.82 (m, 1H), 1.52-1.63 (m, 4H)} 1.31-1.37 (m, 2H), 1.22 (t, 3H), 0.85-0.92 (m, 6H); LCMS: 495 [(M-THP+H)+H]+. Step 3: (E)-3-(4-({E)-2-(3-Butoxyphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl) Phenyl) acrylic 158421.doc -119- 201216961

According to the general procedure F and G from (E)-3-(4-((E)-2-(3-butoxyphenyl)-1-(1-(tetrahydro-2H-.pyran-2-) The title compound was prepared as the title compound as the hydrazinylacetic acid acetoacetate. iH NMR (400 MHz, DMSO-d6): δ 13.11 (bs, 1H), 12.33 (bs, 1H), 8.08 (s, 1H), 7-64 (s, 1H), 7.54 (d, 1H), 7.43 (d, 1H), 7.37 (d, 2H), 7.10- 7.17 (m, 2H), 6.91 (d, 2H), 6.75 (d, 1H), 6.66-6.72 (m, 2H), 6 37 (d, 1H), 3.78 (t, 2H), 2.43 (q, 2H), 1.52-1.60 (m, 2H), 1-29-1.38 (m, 2H), 0.85-0.92 (m, 6H); LCMS: 467 ( M+H)+ 制备Preparation of compound 97 e according to the procedure indicated for compound 96 Example 33: Compound 98 ··(Ε)·3_(4_((Ε) _1(1H STRazole _5 η·. (Methyl Preparation of phenyl) phenyl) butyl _ _ _ 1 yl) phenyl) acrylic acid Step 1: (£)-3-(4-((£)-2-(2-(methyl sulphur) Ethyl)phenyl)(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-yl)butyl-1-ene-1-ylphenyl) acrylate

Prepared according to the general procedure C from intermediate 3, 2-iodothioanisole, and (e)-(4(3-ethoxy-3-oxoxyprop-1-enyl)phenyl)boronic acid Title compound. NMR (DMSO-d6, 300 ΜΗζ): δ 8.14 (s, 1H) 7 75 (d, 1H), 7.72·7_65 (m, 1H), 7.44 (d, 1H), 7.35 (d, 2H) 7.29-7.24 (m, 1H), 7.22-7.11 (m, 3H), 7.09-7.03 (m, 1H) • 120· 158421.doc

201216961 7.01 (d, 2H), 6.44 (d, 1H), 5.85 (dd, 1H), 4.13 (q, 2H), 3.94-3.83 (m, 1H), 3.80-3.68 (m, 1H), 2.47-2.27 (m, 6H), 2.09-1.93 (m, 2H), 1.83-1.69 (m, 1H), 1.67-1.52 (m, 2H), 1.20 (t, 3H), 0.88 (t, 3H). Step 2: (E)-3-(4-((E)-2-(2-(methyl-decyl)phenyl)(tetrahydro-2H-indol-2-yl)-1Η-carbazole- 5-yl)but-1-ene_ι_yl) stupyl) ethyl acrylate

Potassium hydrogen persulfate (521 mg, 0.85 mmol) was added to (E)-3-(4-((E)-2) in MeOH:H.sub.2 (1:1, 6 mL). -(2-(methylthio)phenyl)-1-(1-(tetrahydro-2Η-βΛα南-2-yl)-1Η-σ嗤嗤-5-yl)but-1-嫦-1- A solution of phenyl)ethyl acrylate (156 mg, 0.28 mmol) was added and the reaction was stirred overnight. Water and DCM were added and the layers were separated. The aqueous layer was washed with DCM (x2). The organic layers were combined, washed with water, washed with brine, dried with Na2SOs, filtered and concentrated. The crude material was purified on a silica gel column eluting with 0-50% ethyl acetate in hexane to afford title compound. 1H NMR (DMSO-d6, 300 ΜΗζ): δ 8.15 (s, 1H), 7.91 (d, 1 Η), 7.77-7.71 (m, 2H), 7.49-7.46 (m, 3H)} 7.41-7.31 (m, 4H), 7.01 (d, 2H), 6.45 (d, 1H), 5.87 (dd, 1H), 4.12 (q, 2H), 3.92-3.85 (m, 1H), 3.82-3.69 (m, 1H), 2.93 (s, 3H), 2.46-2.27 (m, 2H), 2.09-1.97 (m, 3H), 1.85-1.67 (m, 1H), 1.63-1.51 (m, 2H), 1.18 (t, 3H), 0.83 (t, 3H). LCMS: 501 [(M-THP+H)+H]+. 158421.doc -121 - 201216961 Step 3: (Ε)-3-(4-((Ε)-1-(1Η-oxazol-5-yl)-2_(2-(methylsulfonyl)phenyl) )but-1-en-1-yl)phenyl)acrylic acid

According to the general procedure F and G from (E)-3-(4-((E)-2-(2-(indolylsulfonyl)phenyl)-1-(1-(tetrahydro-211-pyran) The title compound was prepared from ethyl-2-yl)-111-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylate. 1H NMR (DMSO-d6, 300 MHz): δ 13.14 (brs, 1 Η), 12.29 (brs, 1H), 8.11 (d, 1H), 7.92 (dd, 1H), 7.71 (s, 1H), 7.66-7.54 (m, 2H), 7.53-7.44 (m, 2H), 7.42-7.33 (m, 3H), 7.26 (dd, 1H), 7.01 (d, 2H), 6.34 (d, 1H), 2.94 (s, 3H) ), 2.42-2.30 (m, 2H), 0.83 (t, 3H); LCMS: 473 (M+H)+. Example 34: Compound 99: (E)-3-(4-((E)-l-(lH-indazol-5-yl)-2-indolyl-1-en-1-yl)phenyl) Preparation of -2-methacrylic acid Step 1. (E)-4-(2-Phenyl-1-(1(tetrazol-2 Η- shout-2-yl)-1Η - bite_ 5-base Butyr-1-en-1-yl)benzaldehyde

The title compound was prepared from Intermediate 3, iodobenzene, and (4-mercaptophenyl)boronic acid according to General procedure C. LCMS: 353 [(Μ-ΤΗΡ+Η)+Η]+. Step 2: (Ε)-2-methyl-3-(4-((Ε)-2-phenyl-1-(1-(tetrahydro-2Η-pyran-2-yl)-1Η-carbazole) -5-yl)but-1-en-1-yl)phenyl)ethyl acrylate 158421.doc -122· 201216961

Add 2-(diethoxylate) to a suspension of NaH (80 mg, 2 mmol, 60 °/〇 dispersion in mineral oil) in THF (10 mL) at 〇 °C Stuffed with ethyl acetoacetate (0.36 g, 1.5 mmol). The reaction will be in hydrazine. Stir under the arm for 1 h, and then add (E)-4_(2-phenyl-l-(l-(tetrahydro-2H-pyran-2-yl)-lH-o 引#圭-5-yl) -l-di-l-yl) benzoic acid (0.44 g, 1 mmol) in THF. The resulting mixture was gradually warmed to room temperature and stirred overnight. The reaction mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc. LCMS: 437 [(M-THP+H)+H]+. Step 3: (Ε)-3-(4-((Ε)-1-(1Η-oxazol-5-yl)-2_phenylbut-1-ene·I)phenyl)-2-methyl acrylic acid

According to the general procedure for F and G, (e)-2-methyl-3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2Η-β)-pyran-2 -Based on -1 Η - ° -5-yl)but-1-en-1-yl)phenyl)ethyl acrylate to give the title compound. 1H NMR (300 MHz, DMSO-d6): 5 13.11 (s, 1H), 12.55 (br, 1H), 8.08 (d, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.42 (d , 1H), 7.21-7.11 (m, 8H), 6.90 (d, 2H), 2.40 (q, 2H), 1.92 (d, 3H), 0.87 (t, 3H); LCMS: 409 (M+H)+ . 158421.doc -123- 201216961 Compounds 100 to 109 are prepared from the appropriate boronic acid or phosphonate according to the procedure indicated for compound 99 or the general procedures C, E, F and G. Example 35: Compound 11: (e)-3-(4-((E)-2-(2-Ga-4-fluorophenyl)-1-(1H-indazol-5-yl)butan-1 Preparation of ethyl 1-enyl)phenyl)acrylate: Step 1: (E)-4-(2-(2-Ga-4-fluorophenyl)-1-(1-(tetrahydro) -2H-indol-2-yl)-1Η-indazol-5-yl)but-1-en-1-yl)benzaldehyde

A round bottom flask equipped with a magnetic stir bar, a reflux condenser, an internal thermometer, and an n2 inlet was charged with 5-(but-1- fast-1-yl)-1-(tetrahydro-2H-0 than methane-2 -Base)-1 H-° cited. Sit (50,0 g, 197 mmol; intermediate 3), bis(pentamidine) shed (50.4 g, 199 mmol), and anhydrous 2-indolyltetrahydrofuran (393 mL), followed by Pt (PPh3) ) 4 (1.83 g, 1.5 mmol). This mixture was degassed using three vacuums / n2 %, heated at 8 3 ° C and N 2 (internal temperature; 95 ° C oil bath) for 5 h ' and then cooled to room temperature. 2_曱1 tetrahydrofuran (393 mL), carbolic acid (128.1 g, 393 mmol), and water (11 § mL, 1.5% v/v) were added, and the reaction was cooled to 4 °C. 4 benzophenone age (45.6 g, 197 mmol) and PdCl2 (PPh3) 2 (6·90 g, 9.8 mmol) were added and the reaction was degassed using three vacuum/N2 cycles. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous KOH (4 M, 275 mL, 1100 mmol) and 2- gas-4-fluoro moth (70.6 g, 275 mmol) were added. The reaction was degassed using 3 vacuum / A cycles, heated at 75 ° C and A (internal temperature; 9 〇〇 c 158421.doc • 124 - 201216961 oil bath) for 7 h and then cooled to room temperature. The layers were separated and the organic layer washed with brine (800 mL). The crude product was purified by EtOAc (EtOAc:EtOAc) The main isomer (E)_4_(2_(2_gas_4_fluorophenyl)_丨_(1_(tetrahydro-2H-pyran-2-yl)-1Η-carbazole-5-yl) Data for -1- ene-1-ylbenzaldehyde: 4 NMR (300 MHz, DMSO-d6): δ 9.82 (s, 1H), 8.15 (s, 1H), 7.78-7.71 (m, 2H), 7.61 (d, 2H), 7.43-7.27 (m, 3H), 7.15 (m, 3H), 5.86 (dd, 1H), 3.93-3.85 (m, 1H), 3.79-3.68 (m, 1H), 2.44- 2.36 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.67 (m, 1H), 1.63-1.53 (m, 2H), 0.92 (t, 3H) ; LCMS: 405 [(M-THP+ H)+H]+ » Step 2: (E)-3-(4-((E)-2-(2-Ga-4-fluorophenyl)-1-(1-(tetrahydro-2H-) Ethylpyran-2-yl)-1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate

A round bottom flask equipped with a magnetic stir bar 'addition funnel, and &gt;12 inlet was charged with (E)-4-(2-(2-chloro-4-fluorophenyl)-1-(1-(tetrahydro) -2H-.pyran-2_yl)-1Η-carbazol-5-yl)but-1-en-1-yl)benzaldehyde (82.6 g, 169 mmol), triethyl phosphinoacetate (40.6 mL, 203 mmol), gasification clock (14.5 g, 338 mmol), and anhydrous acetonitrile (338 mL). The reaction was cooled to Ot: and then degassed using three vacuum/N2 cycles. A solution of DBU (27.8 mL, 186 mmol) in acetonitrile (60 mL) was added dropwise over 35 min from 158421.doc -125 - 201216961 and then the ice water bath was removed. The reaction was stirred at room temperature for 1 h, concentrated and then partitioned between dichloromethane (250 mL) and H20 (250 mL). The layers were separated and the organic layer was washed with brine (lilulu The crude product was passed through a silica gel column (300 g, 20% of ethyl acetate), and concentrated to give the title compound (89.6 g). 4 NMR (300 MHz, DMSO-d6): δ 8.14 (s, 1 Η), 7.75 (d, 1H), 7.50-7.33 (m, 6H), 7.27 (dt, 1H), 7.14 (dt, 1H), 6.95 (d, 2H), 6.48 (d} 1H), 5.86 (dd, 1H), 4.14 (q, 2H), 3.94-3.86 (m, 1H), 3.78-3.70 (m, 1H), 2.45- 2.34 (m , 3H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.62- 1.53 (m, 2H), 1.19 (t, 3H), 0.90 (t, 3H) ; LCMS: 475 [( M-THP+H)+H]+ 〇Step 3: (E)-3-(4-((E)-2-(2-Ga-4-fluorophenylcarbazole-5-yl)-but-1- Dil-1-yl)phenyl)ethyl acrylate hydrochloride

I wish Ye Ping Xin Yuanzheng is filled with bottle (E)-3-(4-((E)-2-(2·Ga-4-fluorophenyl) small (1_(tetrachloro-211_〇) domain _2_基)_ 令定_5_基) But-1-en-1-yl)phenyl) acrylate vinegar (255 9 g, 45? 8 and fertilizer solution (732 mL' K25 M, Store in an ethanol towel) ι reaction under a sail for 2.5 h, cool to room temperature, and then concentrate to an organogel. Add a third butyl methyl group (2.3 L). After mixing 5 _, the solid begins to sink. The mixture was stirred at room temperature for 2 h and then filtered. EtOAc (EtOAc) D6): δ 8.11 (s, 1H), 7.69 (s, 1H), 7.57- 7.50 (m, 2H), 7.45-7.33 (m, 4H), 7.21-7.10 (m, 2H), 6.96 (d, 2H ), 6.48 (d, 1H), 4.14 (q, 2H), 2.38 (q, 2H), 1.19 (t, 3H), 0.90 (t, 3H); LCMS: 475 (M+H)+. Preparation of compound lu: (e)_3_(4_((e)_2_(2 chloro-4-tetrafluorophenyl(1H-vava-S-yl)butyl small) phenyl)acrylic acid

Loading a round bottom flask equipped with a magnetic stir bar (E)-3-(4-((E)-2-(2-Ga-4-fluorophenylcarbazole-5-yl)-butane-ene) Phenyl) phenyl hydrazine hydrochloride (198.5 g, 388 mmol; compound 11 oxime) and ethanol (5 17 mL). A solution of LiOH (27.9 g, 1164 mmol) in water (388 mL) was added and the mixture was stirred at room temperature overnight. Ethanol was removed by rotary evaporation and the remaining solution was cooled to EtOAc and acidified to pH 3 using 2M EtOAc. Dichloromethane (5 〇〇 mL) was added, the mixture was stirred and then the layers were separated. The organic layer was washed with water, brine, dried over sodium sulfate. The crude product was passed through a ruthenium dioxide column (8 〇〇 g, 5% Me0H in DCM) and concentrated. The product was then dissolved in mdcm (4 〇〇 mL) to add acetonitrile (10). About mL mL of DCM (solids began to precipitate) was removed by rotary evaporation. Add acetonitrile (55 bark, then add water (25 mL). Stir the mixture at room temperature for 2 h. Evaporate the solvent, 158421.doc •127· 201216961 and then add acetonitrile: DCM (10:1; (mL). Mix the mixture at room temperature for 1.5 h, then pour off the solvent again and then add acetonitrile: dcm (10:1; 550 mL). Mix the mixture again at room temperature for 5 h and then filter The solid was resuspended in acetonitrile: DCM (10:1; 550 mL). DMSO-d6): δ 13.12 (s,1H), 12.34 (br,1Η), 8.11 (d,1Η), 7.69 (s,1Η), 7.56 (d,1Η), 7.44-7.33 (m, 5H), 7.21-7.10 (m, 2H), 6.96 (d, 2H), 6.38 (d, 1H), 2.34 (q, 2H), 0.90 (t, 3H); LCMS: 447 (M+H)+ 〇 Example 37: Compound 112: (E)-3-(4_((E)-2-(2,4-dichlorophenyl)-; i_(1H-indazol-5-yl)but-1-en-1-yl Preparation of ethyl phenyl) acrylate step 1: (Ε)-4-(2-(2,4-diphenyl)-1-(1-(tetrahydro-2Η-»pyran-2-yl) )-1Η-oxazol-5-yl)but-1-en-1-yl Benzaldehyde

A round bottom flask equipped with a magnetic stir bar, a reflux condenser, and an N2 inlet was charged with 5 -(butyl-1 -fast-1 -yl)-1 -(tetrazol-2Η-ηpyran-2-yl) -111 π sitting (20.0 g, 78.6 mmol; intermediate 3), bis(pentamidine) diboron (20.17 g, 79.4 mmol), tetrakis(triphenylphosphine) (0) (0.98 g, 0.8 mmol) And anhydrous 1,4-dioxane (160 mL). This mixture was degassed and refluxed for 4 h using three vacuum/N2 cycles. The solution was then cooled to room temperature, and 4-iodobenzoic acid 18.25 g, 78.6 mmol), trans-diox (triphenylphosphine) le(II) (5·52 g, 7.9 mmol), carbonic acid planing (5 1.24 g, 157.3 mmol), and ι,4- 158421.doc -128- 201216961 dioxane (160 mL). This mixture was degassed using three vacuum/N2 cycles and then water (4.7 mL) was added. The mixture was stirred at room temperature for 6 h. 2,4-Dichloromothene (12.8 mL, 94.4 mmol) and 6 Μ ΚΟΗ aqueous solution (62_9 mL) were added and the mixture was degassed and refluxed for 4 h using three vacuum/N2 cycles. After completion, the reaction mixture was filtered through a pad of Celite / EtOAc and washed with EtOAc. The filtrate was washed with water (600 mL), washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by EtOAc (EtOAc) elute . Data for major isomers: NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1 Η), 8.16 (s, 1H), 7.77 (d, 1H), 7.73 (s, 1H), 7.65 (d, 2H), 7.53 (d, 1H), 7.41-7.36 (m, 2H), 7.31-7.28 (m, 1H), 7.17 (d, 2H), 5.86 (dd, 1H), 3.92- 3.86 (m, 1H) , 3.78-3.71 (m, 1H), 2.47-2.38 (m, 3H), 2.10-1.96 (m, 2H), 1.81-1.71 (m, 1H), 1.64-1.58 (m, 2H), 0.94 (t, 3H); LCMS: 421 [(M-THP+H)+H]+. Step 2: (E)-3-(4-((E)-2-(2,4-diphenyl)-1-(1-(tetrahydro-2H_*pyran-2-yl)-1Η) -oxazol-5-yl)but-1-en-1-yl)phenyl)acrylate

Filled with a round bottom flask equipped with a magnetic stir bar, a rubber septum, and a N2 inlet (E)-4-(2-(2,4-·1 gas-based)-1-(1-(tetrazo- 2H) -0 比喃-2-yl)-1Η-° 丨0坐-5-yl)but-1-ene_1_yl)phenyl hydrazine' (26.7 g, 52.8 mmol), 158421.doc -129- 201216961 Triethyl phosphate (12.7 mL, 63.4 mmol), lithium gasification (4.53 g, 105.7 mmol), and anhydrous acetonitrile (106 mL). The DBU solution (8.7 mL, 58.1 mmo1) in ACN (27 mL) was slowly added dropwise via an addition funnel. The resulting mixture was stirred at room temperature for 4 h. Upon completion, the reaction was concentrated and redissolved in DCM. This solution was washed with water (300 mL), washed with brine (250 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc) : δ 8.14 (s, 1H), 7.75 (d, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 7.43 (d, 2H), 7.37-7.35 (m, 2H), 7.29-7.26 (m,1H), 6.97 (d,2H), 6.48 (d,1H), 5.86 (dd, 1H), 4.14 (q, 2H), 3.91-3.86 (m, 1H), 3.77 -3.71 (m, 1H), 2.48-2.35 (m5 3H), 2.06-1.96 (m, 2H), 1.78-1.71 (m, 1H), 1-62-1.55 (m, 2H), 1.22 (t, 3H ), 0.90 (t, 3H) ; LCMS: 491 [(M-THP+H)+H]+. Step 3: (E)-3-(4-((E)-2-(2,4-diphenyl)-1-(1Η·吲sa_5_yl)but-1-en-1-yl Phenyl) acetoacetate

Add (E)-3-(4-((E)-2-()) to the ethanol (25 mL) in HCl solution (5.0 mL, 2_0 M, stored in 2) at room temperature. 2,4-diphenylphenyl)-1-(1-(tetrahydro-211-&lt;|pyran-2-yl)-111-&quot;bow 丨° sit-5-yl) butyl-1_lean _1_Base) A solution of phenyl) acetoacetate (3.0 g, 5.2 mmol). Mix the resulting -130· 158421.doc

S 201216961 was heated at 70 ° C for 2 h. After completion, the mixture was cooled to room temperature and concentrated to give a pale yellow solid. The crude material was dissolved in DCM and washed with water (50 mL) eluting with brine The crude product was purified by EtOAc EtOAc (EtOAc) A NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 8.11 (s5 1H), 7.69 (s, 1H), 7.58-7.52 (m, 2H), 7.48 (d, 1H), 7.43 ( d, 2H), 7.36-7.32 (m, 2H), 7.19 (dd, 1H), 6.97 (d, 2H), 6.49 (d, 1H), 4.15 (q, 2H), 2.39 (q, 2H), 1.22 (t, 3H), 0.90 (t, 3H); LCMS: 491 (M+H)+. Example 38: Compound 113: (E)-3-(4-((E)-2-(2,4-diphenyl)(1H-indazol-5-yl)but-1-enyl)phenyl ) Preparation of acrylic acid

A solution of LiOH (0.23 g, 9.6 mmol) in water (3.2 mL) was added to (E)-3-(4-((E)-) in EtOH (20 mL) at room temperature. A solution of 2-(2'4-monopropanylpyran-5-yl)but-1-en-1-yl)phenyl)acrylic acid ethyl ester (2.37 g '4.8 mmol; compound 112). The resulting mixture was disturbed overnight. After completion, add 1 N aqueous HCl solution until the pH is 3. The mixture was diluted with water and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (50 mL) EtOAc EtOAc EtOAc The crude product was purified using EtOAc EtOAc EtOAc (EtOAc)咕NMR (400 MHz, DMSO-d6): δ 13.11 (s, 1H), 12 36 (br, 1H), 8.11 (d, 1H), 7.69 (s, 1H), 7.57-7.53 (m, 2H), 7.44-7.35 (m,5H), 7.19 (dd,1H), 6.97 (d,2H), 6.39 (d, 1H), 2.39 (q,2H), 0.90 (t,3H) ; LCMS: 463 (M+ H)+. Compounds 114 to 139 were prepared from the alkynyl-carbazole intermediates according to the general procedures D, E, F, and G. The alkynyl-carbazole intermediate(s) are described herein or prepared according to the general procedure Β and oxime from known or commercially available halocazoles. Example 39. Intermediate Zhao 45: (Ε)-3-(4-((Ζ)·1-(1-(tetrahydro-2H-ylpyran-2-yl)-1Η-carbazol-5-yl)- Preparation of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)but-1-en-1-yl)phenyl)acrylate Step 1 : (Ε)-3-(4-Phenyl)ethyl acrylate

Add Ν-iodosuccinimide (2.5 g, 11 mm〇i) to 4-(E-3-ethoxy-3-side oxygen) in CH/N (50 mL) at room temperature A suspension of phenyl-i-propenyl) phenyl-decanoic acid (2.2 g, 10 mmol). The reaction was covered with a foil, stirred for about 26 hours, and then diluted with EtOAc. The resulting mixture was washed with water (2×100 mL), washed with sodium thio sulfate (EtOAc), dried (MgSO. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc) NMR (400 MHz, DMSO-d6): δ 7.79 (d, 2 Η), 7.60 (d, 1H), 7.53 (d, 2H), 6.68 (d, 1H), 4.19 (q, 2H), 1.26 (t, 3H) ; LCMS: 303 (M+H)+. 158421.doc • 132- 201216961 Step 2: (£)-3-(4-((B)-1-(1_(tetrahydro_211_0&amp; _2_2_yl)_111-oxazol-5-yl) Ethyl -2-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)but-1-en-1-yl)phenyl)acrylate

The title compound was prepared from Intermediate 3 and (yield) 3-(4-iodophenyl)ethyl acrylate. iH NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.70 (d, 1H), 7.58-7.63 (m, 3H), 7.49 (s, 1H), 7.11 (d, 3H), 6.58 (d, 1H), 5.84 (dd, 1H), 4.18 (q, 2H), 3.86-3.91 (m, 1H), 3.70-3.77 (m, 1H), 2.36-2.48 (m, 1H), 2.08-2.15 (m, 2H), 1.95-2.08 (m, 2H), 1.70-1.81 (m, 1H), 1.56-1.62 (m, 2H), 1.25 (t, 3H), 1.12 (s, 12H), 1.01 (t , 3H) ; LCMS: 473 [(M-THP+H)+H]+. Compounds 140 to 144 were prepared from Intermediate 45 according to General Procedure D (Step 3; use of k2C03), F, and G. Example 40: Compound 145: (E)-3-(4-((E)-2-(2-Phenylphenyl)-1-(1-methyl-111-»5丨 -5-5-yl) Preparation of small dilute base) phenyl) acrylic acid

(E)-3-(4-((E)-2-(2-Chlorophenyl)-1-(1Η-indazol-5-yl) in DMF (3.8 mL) at room temperature Addition of methyl iodide to a mixture of but-1-ene-i-yl)phenyl)acrylic acid (8〇mg ' 0.19 mmol ; compound 14) and Cs2C03 (0.15 g, 0.46 mmol) 158421.doc -133· 201216961 Mg, 〇46 mm〇l). The mixture was stirred at room temperature overnight <~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -Methyl·1H_carbazole-5-yl)but-1-ene-1-ylphenyl)decyl ester. Re-dissolve this residue in thf_

An aqueous solution of LiOH (89 mg, 3.7 mmol; dissolved in a minimum of water) was added in MeOH (3.8 mL) at room temperature. The reaction mixture was stirred with EtOAc EtOAc m. Use 50-100 in water on the RP_C18 column. /. The crude product was purified using acetonitrile in the presence of EtOAc (1%) to afford title compound. 1H NMR (300 MHz, DMSO-d6) J 12.28 (s, 1H), 8.07 (s, 1H), 7.67-7.64 (m, 2H), 7.48-7.11 (m, 8H), 6.95 (d, 2H), 6.35 (d, 1H), 4.05 (s, 3H), 2.36 (q, 2H), 0.90 (t, 3H). LCMS: 443 (M+H) + ° Example 41: Compound 146: (E)_3_(4_((E)_2, butyl small (1 methyl-1 Η-β5丨 -5-5-yl)-2-benzene Preparation of vinylidene)phenyl)acrylic acid Step 1: (E)-3-(4-((E)-2-cyclobutyl-1-(1-methyl_iH_〇) 5_yl)_2-phenylvinyl)phenyl)ethyl acrylate

Adding terpine (80 mg, 0.84 mmol) to (E)-3-(4-((E)-2-cyclobutyl-1·(ιη-, oxazol-5-yl) at room temperature Ethyl 2-phenylvinyl)phenyl)acrylate (0.25 g, 0.56 mmol; intermediate in compound 84), K2C03 (0.12 g, 0.84 mmol), and DMF (5.6 mL). The resulting mixture was stirred overnight, diluted with water and used 158421.doc •134- 201216961

Et0Ac extraction. The extract was washed with water, washed with brine, dried over NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH LCMS: 463 (M+H)+. Step 2: (E)-3-(4-((E)-2-cyclobutyl·1·(1_methyl-1H-carbazole-5-yl)-2-phenylvinyl)phenyl)acrylic acid

(E)-3-(4-((E)-2-cyclobutyl-1-(1-methyl-lH-i.sodium-5-yl)-2-benzene) as described in General Procedure G The title compound is prepared by the ethyl vinyl)phenyl)ethyl acrylate. 1H NMR (400 MHz, DMS0-d6): δ 12.26 (s, 1H), 8·〇6 (s, 1Η), 7.68-7.61 (m, 2Η), 7·37 (d, 1Η), 7.31-7.12 (m, 8H), 6.92 (d, 2H), 6.36 (d, 1H), 4.09 (s, 3H), 3.46-3.39 (m, 1H), 1.84-1.76 (m, 4H), 1.63-1.52 (m , 1H), 1.37-1.32 (m, out); LCMS: 435 (M+H)+. Compound 147 was prepared according to the procedure indicated for compound 146. Example 42: Compound 148 : (E)-3-(4-((E)-2-(2-Ga-4-fluorophenyl)-1-(1-(difluoromethyl)-1Η-carbazole Preparation of -5-yl)but-1-en-1-yl)phenyl)acrylic acid

(Ε)-3-(4-((Ε)-2·(2-Ga-4_fluorophenyl)-1-(1Η-carbazole·5-yl)) in DMF (1 mL) A solution of ethyl-1-enyl-indole-yl)phenyl)acrylate (1〇5 mg, 〇·22 mm〇i; the free base of the compound 丨1〇) was added to DMF 158421.doc -135 - 201216961 Suspension t of sodium hydride (11 mg, 0. 27 mmol) in (1 mL). The mixture was stirred at room temperature for 1 h, and then difluoroiododecane was bubbled through 1 〇 min. The reaction mixture was heated at 80 ° C for 3 h and cooled to room temperature. The difluoroiododecane was bubbled again for 10 min and the mixture was heated for an additional 1.5 h. The reaction mixture was cooled to EtOAc EtOAc (EtOAc)EtOAc. The crude material is purified on a ruthenium hose column to produce a mixture containing the desired intermediate. LCMS: 525 (M+H)+. According to the general procedure G, this intermediate will give the title compound. 1H NMR (300 MHz, DMSO_d6): δ 8.91 (s, 1H), 8.17 (t, 1 Η), 7.77 (s, 1H), 7.74 (d, 1H), 7.45-7.35 (m, 5H), 7.20 (dd , 1H), 7.15 (dt, 1H), 7.00 (d, 2H), 6.38 (d} 2H)S 2.41 (q,2H),0.92 (t,3H) ; LCMS: 497 (M+H)+ » Examples 43: 3x ERE MCF-7 reporter analysis maintains MCF7 cells in RPMI 1640 supplemented with 10% FCS. Transcription analysis was carried out by inoculating 100 μM cells at a density of 250,000 cells/mL into 96-well cell culture plates (stored in RPMI 1640 supplemented with 10% charcoal-treated serum) and allowed to bind overnight. Cells were transiently transfected using Lipofectin (Life Technologies) according to the manufacturer's protocol. Triplicate transfections were performed using 300 ng of 3X ERE-TK-Luc (reporter vector), 50 ng of CMVpRL (normalized vector), and 130 ng of pCMX (filled DNA). The transfected cells were incubated overnight and then treated with ligand. For ER agonist analysis, compounds were serially diluted and 50 pL of compound plus RPMI 1640 supplemented with charcoal-treated serum was added to the cells. For ER antagonist analysis, compounds were serially diluted and 50 μM compound was added to the cells with 158421.doc -136·201216961 RPMI plus carbon-treated serum supplemented with 17β-estradiol. The final 17β-estradiol concentration used in the antagonist analysis was 0.1 ηΜ. After 24 hours of incubation, the medium was removed and cells were lysed in 40 pL lysis buffer (25 mM Tris phosphate, 2 mM CDTA, 10% #*, 0.5% Triton X-100, 2 mM DTT). Add 40 pL luciferase buffer (20 mM tris(hydroxymethyl)methylglycine, 〇_1 mM EDTA, 1.07 mM (MgCo3)4 Mg(OH), · 5H20, 2.67 mM MgSCU, 33.3 mM Firefly luciferase activity was measured immediately after DTT, 270 μΜ CoA, 470 μΜ luciferin, 530 μΜ ATP. Add 40 kL of coelenterazine buffer (1.1 M NaCl ' 2.2 mM Na2EDTA, 0.22 M KxP04 (pH 5.1), 0.44 mg/mL BSA, 1.3 mM NaN3, 1.43 μΜ coelenterazine. Final pH adjustment to 5.0) Sea kidney luciferase was measured. Example 44: Breast cancer cell survival analysis The concentration of MCF-7 cells in RPMI containing 10% FBS and 20 mM HEPES was adjusted to 20,000 cells/mL. Sixteen microliters of cell suspension (320 cells) was added to each well of a 384-well plate, and the cells were incubated overnight to allow attachment of the cells. On the next day, an 11-point serial half-difference of each compound was added to a 16 pL cell suspension with a final concentration between 0.3-0.000003 μΜ. After 5 days of compound exposure, 16 pL of CellTiter-GLo (Promega, Madison WI) was added to the cells and the relative fluorescence units (RLU) of each well were determined. Background values were obtained using CellTiter-Glo added to a 32 pL cell-free medium. The percent survival of each sample was determined as follows: (sample RLU - background RLU / RLU of the untreated cells - background RLU) X 1 〇〇 = % survival. 158421.doc • 137· 201216961 Survival effects in other ER+ breast cancer cell lines (including BT474, CAMA1, MDA-MB-361, ZR-75-1, T47D) can be described in an analysis similar to Example 44. Example 45: In Cell Western Assay (SPl) of breast cancer cells ER-α The concentration of MCF-7 cells in RPMI containing 10% charcoal-treated FBS and 20 mM HEPES was adjusted to 200,000 cells/mL· . Ten microliters of the cell suspension (3200 cells) was added to each well of a poly-D-lysine 384-well plate, and the cells were incubated overnight to allow attachment of the cells. On the next day, an 11-point semi-log dilution of each compound was added to the 16 kL cell suspension with a final concentration between 0.3-0.000003 μΜ. After addition of the compound for 4 or 24 hr, the cells were fixed (10% formalin in PBS) for 20 minutes. The cells were immersed in PBS 0.1% Triton and blocked with LICOR blocking buffer (50 μΐ/well, 90'). The wells were then incubated overnight at 4 °C with SP1 rabbit monoclonal Ab (Thermo Scientific) diluted 1:1000 in LICOR blocking buffer / 0.1% Tween-20. Wells treated with Tween but no antibody blocking buffer were used as background controls. Each well was washed with 0.1% Tween-20/PBS and then in goat anti-rabbit IRDyeTM 800CW (LICOR; 1:1000) and DRAQ5 DNA dye (1:2000 for 2 mM stock) (with 0.1 Incubate for 60 minutes in % Tween-20 and 0.01% SDS in LICOR blocking buffer. The cells were washed in 0.1% Tween-20/PBS (50 μΐ/well, each 5·). The plate was scanned on a LICOR Odyssey Red Image Imaging System. Measure the integrated intensity in 800 nm channel and 700 nm channel to determine the content of ER and DNA, respectively. 138· 158421.doc

S 201216961 quantity. Determine the percentage of ER content as follows: (integrated intensity of 800 nm sample / integrated intensity of 700 nm sample) / (integral intensity of 800 nm untreated cells / integrated intensity of 700 nm untreated cells) χ 100 = £ 11% by content. The effect of the steady-state content of ER-α in other ER+ breast cancer cell lines (containing ΒΤ474, CAMA1, MDA-MB-361, ZR-75-1, T47D) can be described in an analysis similar to Example 45. Exemplary biological data for representative compounds disclosed herein are presented in Table 7. Table 5. Maximum response of MCF7 survival analysis of compound MCF7 survival analysis IC50 ER-a cells of ER-a intracellular Western analysis (SP1) Maximum response of internal analysis (SP1)

158421.doc -139- 201216961 25 A ++ A ++ 26 A ++ A ++ 27 A ++ A ++ 28 A ++ A ++ 29 A ++ A ++ 30 A ++ A ++ 31 A ++ A ++ 32 A ++ A ++ 33 A ++ A ++ 34 A ++ A ++ 35 A ++ A ++ 36 A ++ A ++ 37 A ++ A ++ 38 B ++ B ++ 39 B ++ B ++ 40 B ++ B ++ 41 A ++ A ++ 42 A ++ A ++ 43 A ++ A ++ 44 A ++ A ++ 45 A + + A ++ 46 B + B ++ 47 A ++ A ++ 48 A ++ A ++ 49 A ++ A ++ 50 A ++ A ++ 51 A ++ A ++ 52 A ++ A ++ 53 A ++ A ++ 54 A ++ A ++ 55 A ++ A ++ 56 A ++ A ++ 57 A ++ A ++ 58 A ++ A ++ 59 A ++ A + + 60 A ++ A ++ 61 A ++ A ++ 62 A ++ A ++ 63 A ++ A ++ 64 A ++ A ++ 65 A ++ A ++ 66 A ++ A ++ 158421.doc -140- s 201216961 67 A ++ A ++ 68 A ++ A ++ 69 A ++ A ++ 70 A ++ A ++ 71 A ++ A ++ 72 A ++ A ++ 73 A ++ A ++ 74 A ++ A ++ 75 A ++ A ++ 76 A ++ A ++ 77 A ++ A ++ 78 A ++ A ++ 79 A ++ A ++ 80 B ++ A ++ 81 B ++ A ++ 82 A ++ A ++ 83 A ++ A ++ 84 A ++ A ++ 85 A ++ A ++ 86 A ++ A ++ 87 A ++ A ++ 88 A ++ A ++ 89 A ++ A ++ 90 A + A ++ 91 A + - - 92 A + - 93 A ++ A ++ 94 B ++ A ++ 95 A ++ A ++ 96 A ++ A ++ 97 A ++ A ++ 98 A ++ A ++ 99 A ++ A ++ 100 A ++ A ++ 101 A ++ A ++ 102 A ++ A ++ 103 B ++ A ++ 104 B ++ A ++ 105 A ++ A ++ 106 A ++ A ++ 107 B ++ A ++ 108 A ++ A ++ 158421.doc -141 - 201216961 109 A ++ A ++ 110 A + A ++ 111 A ++ A ++ 112 A + A ++ 113 A ++ A ++ 114 A ++ A ++ 115 A ++ A ++ 116 A ++ A ++ 117 A ++ A ++ 118 A ++ A ++ 119 A ++ A ++ 120 A ++ A + + 121 A ++ A ++ 122 A ++ A ++ 123 A ++ A ++ 124 A ++ A ++ 125 A ++ A ++ 126 A ++ A ++ 127 B + B + 128 A ++ A ++ 129 A ++ A ++ 130 A ++ A ++ 131 B ++ B ++ 132 A ++ A ++ 133 B + B ++ 134 A ++ A ++ 135 A ++ A ++ 136 A ++ A ++ 137 A ++ A ++ 138 A ++ A ++ 139 A ++ A ++ 140 A ++ A ++ 141 B ++ A ++ 142 A ++ A ++ 143 B ++ A ++ 144 A ++ A ++ 145 A ++ A ++ 146 A ++ A ++ 147 A ++ A ++ 148 A ++ A ++ A=Single IC5〇S100 nM ; B = single IC5 〇 &gt; 100 nM ; + = single % • 142 - 158421.doc

S 201216961 value &lt;40% ; ++ = single % value &gt; 40% Example 46: Ishikawa uterine cell assay for acid-filled yeast analysis will be stored in T225 as fast as Ishikawa cells in estrogen-free basal medium (EFBM) (Cultivated by DMEM containing 5% FBS treated with carbon dextran and 20 mM HEPES: Ham's F-12 50:50 phenol red free base medium) for 24 hours. On the next day, cells were plated in EFBM in clarified 384-well plates at a concentration of 2·5 X 105 cells/mL, 16 pL/well (4000 cells/well). Each compound was subjected to a 12-point semi-log dilution in DMSO and subsequently diluted in EFBM. Immediately after tiling the cells, an equal volume of the compound present in the EFBM was added and the cells were incubated for 3 days. Cells were fixed using 5% formalin and rinsed with PBS. The alkaline phosphatase-bearing 4-nitrophenyl phosphate disodium salt hexahydrate was added to a solution containing 2 mM MgCl 2 , 1 Μ diethanolamine, and adjusted to pH 9.0. The substrate was added to the cell culture medium (16 μ! 7 well), and the optical density of the cells treated with 17β-estradiol (concentration range 1-30 ηΜ) at a wavelength of 405 nm reached 1.0-1.2 absorbance. In units, the OD405 is measured in a multi-wall spectrophotometer. Cells treated with DMSO alone were used as background controls. The percentage of activity in the background subtracted sample is measured as follows: % active = OD405 of the sample / maximum OD405 X 100 of the cells treated with 17β-estradiol. Example 47: Egg yolk cancer cell survival rate analysis The concentration of BG-1 cells in RPMI containing 10% FBS and 20 mM HEPES was adjusted to 20,000 cells/mL. Sixteen microliters of cell suspension (320 cells) was added to each well of a 384-well plate, and the cells were incubated overnight to allow attachment of the cells. On the next day, a 11-point serial half of each compound was added to a 16 pL cell suspension with a final concentration between 0.3-0.000003 μΜ. After 5 days of exposure of the compound, 16 μ!^ CellTiter-GLo (Promega, Madison WI) was added to the cells, and the relative fluorescence units (RLU) of each well were measured. Background values were obtained using CellTiter-Glo added to a 32 μί cell-free medium. The percent survival of each sample was determined as follows: (sample RLU - background RLU / RLU of untreated cells - background RLU) X 100 = viability. /〇. Survival effects in other ER+ ovarian cancer cell lines (including A1847, SKOV3, SW626, A2780) can be described in an analysis similar to Example 47. Example 48: Western analysis of ER-α cells in ovarian cancer cells The concentration of BG-1 cells in RPMI containing 10% charcoal-treated FBS and 20 mM HEPES was adjusted to 200,000 cells/mL. Sixteen microliters of cell suspension (3200 cells) was added to each well of a poly-D-lysine 384-well plate, and the cells were incubated overnight to allow attachment of the cells. On the next day, add 11-point serial half-log dilutions of each compound to the 16 μL cell suspension and the final concentration was between 0.3-0.000003 μΜ. After adding the compound for 4 or 24 hr, the cells were fixed (stored in 10% formalin in PBS for 20 minutes. Cells were immersed in PBS 0.1% Triton and blocked with LICOR blocking buffer (50 μΐ/well, 90'). Wells were then incubated overnight at 4 °C with ER1D5 (Santa Cruz Biotechnology) diluted 1:100 in LICOR Blocking Buffer/0.1% Tween-20. Wells treated with Tween but no antibody blocking buffer were used as background controls. Each well was washed with 〇. 1% Tween-20/PBS, and then in goat anti-mouse IRDyeTM 800CW (LICOR; 1:1000) and DRAQ5 DNA dye (1:2000, 158421.doc -144- 201216961 for 2 For mM stocks) (diluted in LICOR blocking buffer containing 〇i% Tween-20 and 0.01% S〇S) for 60 minutes. The cells were washed in 〇·1% Tween-20/PBS (50 μΐ/well, each 5). Scan the board on the LICOR Odyssey infrared imaging system. The integrated intensities in the 800 nm channel and the 700 nm channel were measured to determine the ER and DNA content, respectively. As shown below, the percentage of ER content: (integrated intensity of 800 nm sample / integrated intensity of 700 nm test) / (integral intensity of 800 nm untreated cells / integrated intensity of 700 nm untreated cells) x 1 〇〇 = ER content ° / 〇. The steady-state accountability of ER-ct in other ER+ ovarian cancer cell lines (including A1847, SKOV3, SW626, A2780) can be described in an analysis similar to Example 48. Other cancer cell lines encompassing the compounds described for the test include ER-positive endometrial cell lines (Ishikawa, ECC1, HEC-1 EnCa-101) and ER-positive cervical cell lines (Caski, HeLa, SiHa). ° Example 49: Breast Cancer Model: Xenograft Analysis (MCF-7) A timed release pellet containing 0.72 mg of 17-[beta] estradiol was percutaneously implanted into nu/nu mice. MCF-7 cells were grown at 5% C〇2 '37 °C in RPMI containing 10% FBS. The cells were spun and suspended in 50% RPMI (serum free) and 50 &lt; 5/° Matrigel at IX 1 〇 7 cells. MCF-7 cells were injected subcutaneously (ΙΟΟμυ animals) to the right wing 2-3 days after implantation of % private. Tumor volume (length χ width 2/2) was monitored every two weeks. Animals were randomized and started to cure when the swelling reached an average volume of approximately 200 mm3. Animals were treated daily with vehicle or compound for 4 weeks. Tumor volume and body weight were monitored every two weeks throughout the pray. At the end of treatment time 158421.doc -145- 201216961, plasma and tumor samples were obtained for pharmacokinetic and pharmacodynamic analysis, respectively. Examples: breast cancer model against tamoxifen; xenograft analysis (MCF-7 derivative) treatment of MCF-7 tumors (mean tumor volume) by oral gavage using tamoxifen (citrate) Female nu/nu mice of 200 mm3) (using supplemental 17-beta estradiol sinking; 〇.72 mg; slow release over 6 days). Tumor volume (length x width 2/2) and body weight were monitored twice a week. After a significant anti-tumor response in which the tumor volume remained constant, a significant tumor growth was first observed under about 1 day of treatment. After 12 days of treatment, the tamoxifen-incorporating tumors with tacrolimus growth had tamoxifen resistance and were selected for use in the tongue to pass on new host animal orders. Tumor sections from tamoxifen-resistant tumors (approx! 〇〇mm3/animal) were subcutaneously implanted into the stagnation/sinus mice (using 17·β estradiol precipitate (〇72 mg; 6 〇 days) Slow release of the right wing. The tamoxifen was selected to maintain the passage of the tumor, and the tumor volume was monitored weekly (length X width/2). When the tumor volume reached about 150-250 mm3, the animals were randomly assigned to the treatment group. (mean tumor volume was 2〇〇mm3) and termination of tamoxifen treatment (except for the tamoxifen control group). Animals were treated daily with vehicle or compound for 4 weeks. Monitoring was performed every two weeks during the study period. Tumor volume and body weight. At the end of treatment time, blood collection and tumor samples were obtained for pharmacokinetic and pharmacodynamic analysis. Example 51 · Nested cancer model; xenograft analysis (BG-1) The timed release of Shen Dian (0.72 mg 17·ρ estradiol / 60 days) was implanted subcutaneously in the presence of I· raw nu/nu in a small gas. In the presence of l〇% fBS, 1〇mM sodium pyruvate, 158421. Doc

S •146- 201216961

BG-1 cells were grown in DMEM Ham's F-12 50/50 of 10 mM non-essential amino acids at 5% C 〇 2, 37 ° c. The cells were spun and resuspended in 50% DMEM Ham's F-12 (serum free) and 50% Matrigel at 5X107 cells/mL. BG-1 cells were injected subcutaneously (100 μ; ί/animal) to the right wing 2-3 days after implantation of the pellet. Tumor volume (length X width 2/2) was monitored every two weeks. When the tumor reached an average volume of approximately 250 mm3, the animals were randomized and treatment started. The vehicle or compound is used to treat the animal daily for 4 weeks. Tumor volume and body weight were monitored every two weeks throughout the study. At the end of the treatment period, plasma and tumor samples were taken for drug metabolism kinetics and pharmacodynamic analysis, respectively. Example 52: Immature Uterine Wet Weight _ Antagonist Mode Female immature CD-IGS rats (21 days old upon arrival) were treated with the mother for one day in three days. The drug was administered orally by means of gavage or the compound of the formula was administered, and 15 minutes later, the oral administration amount of mg.1 mg/kg ethinyl estradiol was administered. On day 4, at 24 hours after administration, plasma was collected for pharmacokinetic analysis. Immediately after the plasma was collected, the animals were euthanized and the uterus was removed and weighed. Example 53: Immature uterus wet weight _ agonist mode Female immature CD-IGS rats (21 days old upon arrival) were treated for three days. Each animal is administered to the animal within three days. # Oral administration of vehicle or test compound by gavage, and a second oral dose of vehicle after 15 minutes. On day 4, at 24 hours after administration, plasma was collected for pharmacokinetic analysis. Immediately after the "paste", the animals were euthanized and the uterus was removed and 158421.doc • 147· 201216961 Example 54: Breast Cancer Clinical Trial Purpose: The purpose of this study was to evaluate the use of a compound of formula (1), or a pharmaceutically acceptable salt thereof. To treat the efficacy of metastatic breast cancer, to collect information on any side effects that can be caused by the compound of formula (1), or a pharmaceutically acceptable salt thereof, and to evaluate the pharmacokinetic properties of the compound of formula (1), or a pharmaceutically acceptable salt thereof Measure: 15 mg/kg of a compound of formula (1), or a pharmaceutically acceptable salt thereof, administered to a patient twice daily or twice a day. Measure of results: main result measure: for a compound of formula (1), or a pharmaceutically acceptable compound thereof For the treatment of salt as one of the patients with estrogen receptor (ER)-positive metastatic breast cancer, the primary outcome measure is the patient's tumor response and/or disease control. Secondary outcome measure: secondary outcome Measure the side effects of the compound of formula (1), or a pharmaceutically acceptable salt thereof; (b) evaluate the drug metabolism of a compound of formula (1), or a pharmaceutically acceptable salt thereof Kinetic properties; (c) assessment of the proportion of patients with complete or partial response or stable disease at defined time points; (d) assessment of progression and overall survival of patients treated with a compound of formula (1), or a pharmaceutically acceptable salt thereof And (e) biomarkers for predicting clinical response. Detailed Description: Oral administration of a compound of formula (1), or a pharmaceutically acceptable salt thereof, orally or once or twice a day. Compound of formula (1) or its medicinal Physical examination, blood test, and evaluation of any side effects are performed prior to each administration cycle of acceptable salt. Every 12 weeks, the patient's cancer is reassessed using CT scan or MRI to determine if the treatment is working. Continue to participate in the study until 158421.doc -148- 201216961 Disease progression or unacceptable toxicity. Compliance: Female, 18 years and older. Inclusion criteria: Histologically or cytologically confirmed diagnosis of invasive breast cancer, stage iv Disease. At least one measurable target lesion defined by RECIST is not treated with topical therapy. Post-menopausal status. Positive breast cancer. HER2- Sexual breast cancer. For advanced or metastatic disease, with at most one prior hormone therapy. EC0G physical status is. Life expectancy &gt; 12 weeks. Has appropriate liver and bone marrow function: AST &lt; 2 5xULN; bilirubin &lt;1.5xULN;ANC&gt;1,500/U1; platelet count &gt; 1 〇〇〇〇〇 / ul; with normal PT and PTT. Recovered from previous radiation for at least 2 weeks, and self-treatment-related toxicity. Exclusion criteria: HER2-positive breast cancer. Previous chemotherapy regimen for metastatic disease. Has a history of brain metastasis, or presence of brain metastases. Simultaneous test drug treatment. Previous bone marrow or stem cell transplant. Has a history of other malignant tumors in the last 5 years, does not include the child of curative treatment Cervical carcinoma in situ or non-melanoma skin cancer. Uncontrolled infection. Active bleeding, or a history of bleeding that requires blood transfusion. Active heart disease" is a serious medical or psychiatric condition. Example 55: Parenteral Pharmaceutical Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 100 mg of a compound of formula (I) or a water-soluble salt of a compound of formula (1) is dissolved. Mix in sterile water and then with 10 mL of 0.9% sterile saline. The mixture is included in a dosage unit form suitable for administration via injection. In another embodiment 10, the following ingredients are combined to form an injectable formulation: 158421.doc -149 - 201216961 1.2 g of a compound of formula (1), or a pharmaceutically acceptable salt thereof, 2 mL of a sodium acetate buffer solution (0.4 M ), HC1 (1 (1 M) (to make up to the appropriate pH), water (distillation, sterile) (supplement to 2 〇 mLp combine all the above ingredients except water, and mix, and if necessary, slightly heat. Then Sufficient water is added.Example 56: Oral solution To prepare a pharmaceutical composition for oral delivery, a 20% aqueous solution of propylene glycol is prepared. A sufficient amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, is added to the solution to provide 2 mg/mL solution. Example 57: Oral Capsule To prepare a pharmaceutical composition for oral delivery, 1 〇〇 5 mg of the compound of formula (1), or a pharmaceutically acceptable salt thereof, is mixed with starch, The mixture is incorporated into an oral dosage unit suitable for oral administration such as a hard gelatin capsule. In another embodiment, 100-500 mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is placed in capsule No. 4 , or No. 1 capsule (hydroxypropyl cellulose or hard Capsules and sealed capsules. Example 58: Oral lozenges by mixing 48% by weight of a compound of formula (I), or a pharmaceutically acceptable salt thereof, 45 % by weight of microcrystalline cellulose, 5 parts by weight of ❶/◦ The tablet is prepared by low-substituted propylcellulose and 2% by weight of magnesium stearate. The tablet is prepared by direct compression. The total weight of the compressed tablet is maintained at 250-500 mg. Example 59: Partial The gel composition is a preparation of a pharmaceutical topical gel composition, the compound of the formula (I), or a pharmaceutically acceptable salt thereof, and hydroxypropylcellulose, propylene glycol, isopropyl myristate 158421.doc -150 - 201216961 The vinegar and the purified alcohol USP are mixed. The resulting gel mixture is then portioned into a container (eg, a tube). The examples and examples described herein are for illustrative purposes only and are various modifications suggested by those skilled in the art or The changes are included in the scope of the Chinese God and the scope of the patent application. The application is suitable for the practice of this project. 158421.doc -151 -

Claims (1)

201216961 VII. Scope of Application: 1. A compound of formula (1), or a pharmaceutically acceptable salt thereof, or an N-oxide, TM Jp R〇 〇 Z Formula (I) wherein z is -OH or -OR10; R2 is Ci-C4 alkyl, C丨-C4 fluoroalkyl.丨-(: 4氘 alkyl, C3-C6 cycloalkyl, or -C1-C4 extension)-W; w-hydroxy, halogen, CN, Ci-C4 alkyl, Cl_c4_alkyl, Cl·C4 Alkoxy, CVC4 halo alkoxy, or c3_c6 cycloalkyl; each R is independently halogen, C1-C4 alkyl, or fluoro, and each R4 is independently halogen, -CN, -OR9, _s(= C);) 2R10, alkyl, CVC4 fluoroalkyl, or heteroalkyl; each R5 independently is dentate, _CN, _0R9, _s(=〇)2Rl. , Ci_C4 alkyl, CVC4 fluoroalkyl, or Ci-Q heteroalkyl; R Η, C!-C4 alkyl, or halogen; R Η, C1-C4 alkyl, or halogen; R9 H, Cl -C6 alkyl, Cl_c6 fluoroalkyl, or 匕-^cycloalkyl; R10 based CrCe alkyl; m is 0, 1, or 2; η is 0, 1, 2, 3, or 4; and 158421.doc , 201216961 p is 0, 1, or 2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a cerium-oxide, wherein: lanthanide-oxime; R6 lanthanum, -CH3, F, or C1; R7 lanthanum, -CH3, F, or Cl; each R3 is independently halogen, (^-(:4 alkyl, or fluoroalkyl; each R4 is independently halogen, -CN, -OH, -OR9, -S(=0)2R10, C!-C 4 Hyun, C 1 -C 4 fluoroalkyl, c 1 - C 4 heteroalkyl, c 1 - C 4 fluoroalkoxy, or C 1 - C 4 Hyun &gt;oxy; R5 is independently halogen, &lt;:丨-(:4 alkyl, or Ci-C4 fluoroalkyl; m is 0 or 1; η is 0, 1 or 2; and ρ is 0 or 1. 3. The compound of Item 1 or 2, or a pharmaceutically acceptable salt thereof, or a cerium-oxide thereof, wherein: R2 is CVC4 alkyl, CVC4 fluoroalkyl, CVC4 decyl, C3-C6 cycloalkyl, or -CVC4 alkyl-W; W-hydroxy, halogen, CN, (VC4 alkoxy, or C3-C6 cycloalkyl. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, or N-oxidation And wherein: Z series - OH; R6 system Η; R7 system Η; 158421.doc 201216961 n is 0, 1 or 2; and ρ is 0. 5 * The compound of claim 1, wherein The compounds of formula (I) has ([pi) of the structural formula, or a pharmaceutically acceptable salt thereof, or an oxide Ν-: Formula (II). 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, or a cerium-oxide, wherein: each R3 is independently F, C1, or -CH3; each R4 is independently halogen, -CN, _ 〇H, _S(=0)2CH3, -S(=0)2 CH2CH3 ' -CH3 ' -CH2CH3 ' -CF3 ' -CH2OH &gt; -OCF3 &gt; -OCH3 &gt; or -〇CH2CH3 ; each R5 is independently F, Cl, or -CH3; m is 0 or 1; n is 0, 1 or 2; and ρ is 0 or 1. 7. The compound of claim 5 or 6, or a pharmaceutically acceptable salt thereof, or a cerium oxide, wherein: -CH(CH3)2, -CH2CH2CH2CH3, 2'-CF3, -CH2CF3, -cd3, R2 is -CH3, -CH2CH3, -CH2CH2CH3, -α-CH2CH(CH3)2, _CH2f'_CHF2, 158421.doc 201216961 -CHWD3, -CD2CD3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, - CH2-W, or -CH2CH2-W; w-hydroxyl, F, cn, _CN, -och3, _OCH2CH3, -〇CH2 ch2ch3, -och(ch3)2, cyclopropyl, cyclobutyl, cyclodecyl, or Cyclohexyl. 8. The compound of claim 5, or a pharmaceutically acceptable salt thereof, or an antioxidant thereof, wherein: R2 is -CH2CH3; each R4 is independently F, alpha, -CN, ??, -CH3, -CH2CH3 , -CF3, -CH2〇H, -OCF3, -OCH3, or -OCH2CH3; m is 0; n is 0, 1 or 2; and p is 0. 9. The compound of claim 1, wherein the compound is: (e)-3-(4-((E)-1-(1H-indazol-5-yl)-2-phenylbut-1-ene) Ethyl-1-yl)phenyl)acrylate, (Ε)-3-(4-((Ε)-1-(1Η-oxazol-5-yl)-2·phenylbut-1-ene-1 -yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)·2-(4-fluorophenyl)-1-(1Η-indazol-5-yl)but-1-ene- 1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(4-phenylphenyl)-1-(1H-indazol-5-yl)but-1-ene- 1-(yl)phenyl)acrylic acid, (E)-3-(4-((E)-l-(lH-indazol-5-yl)-2-(3-decyloxyphenyl)butane-1 -en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(3-(hydroxymethyl)phenyl)-l-(lH-carbazole-5- Butyl-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)·2-(4-(hydroxyindenyl)phenyl)-1-(1Η- Oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-(2-(hydroxymethyl)phenyl)-) 1-(1Η-oxazol-5-yl) 4- 158421.doc S 201216961 But-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1- (1Η-carbazol-5-yl)-2-(o-tolyl)but-1-en-1-yl)phenyl)acrylic acid, (magic-3_(4-((E)-1-) 1H-carbazol-5-yl)-2-(m-decylphenyl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-( 1Η-carbazol-5-yl)-2-(p-tolyl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(1Η) -carbazol-5-yl)-2-(2-decyloxyphenyl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((Ε)-1 -(1Η-oxazol-5-yl)-2-(4-decyloxyphenyl)but-1-ene-buyl)phenyl)acrylic acid, ((E)-3-(4-((E )-2-(2-chlorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-(( E)-2-(3-Phenylphenyl)-1-(1Η-.azole-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4- ((E)-2-(2-Fluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4 -((E)-2_(3-fluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4 -((E)-2-(2-ethylphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3- (4-((Ε)-1·(1Η-吲嗤-5-yl)-2-(2-(trifluoromethyl)phenyl)but-1-ene-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-4 -Chloro-1-(1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2 -(2-cyanophenyl)-1-(1Η-β5丨嗤-5-yl)but-1-en-1-yl)phenyl)propionic acid, (ugly)-3-(4-( (£)-2-(2,4-diphenyl)-1-(111-5*). Sodium-5-yl)butyl-1-indol-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-(2-chloro-3-fluorophenyl)); [·(111-'1 嗤-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (£)_3-(4-((E)-2-cyclopropyl-1- (1H-carbazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(4-fluoro-2-methylphenyl) Salivation _5-yl)but-1-en-1-yl)phenyl)propionic acid, (E)-3-(4-((E)-2-(2,6-digas 158421.doc 201216961 Phenyl)-1-(1Η-oxazol-5-yl)but-1-ene-byl)phenyl)acrylic acid, (E)_ 3-(4-(( 丑)-2-(2,6 -diphenyl)-1-(111-carbazole-5-yl)but-1-ene-byl)phenyl)acrylic acid, (E)-3-(4-((E)-4,4 , 4-tricarbazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(4) -fluoro-3-indolylphenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl) acrylic acid, (ugly)-3-(4-((ugly )-2-(5-fluoro-2-indolylphenyl)-1-(1Η-吲 ··5·yl)butan-1·en-1-yl)phenyl)acrylic acid, (E)-3- (4-((E)-2-(2,3-difluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E )-3-(4 -((E)-2-(2,5-difluorophenyl)-l-(lH-indazol-5-yl)butan-1-yl-l-yl)phenyl)acrylic acid, (E)- 3-(4-((E)-2_(2-Ga-5-fluorophenyl)-bu(lH-indazol-5-yl)butyl-:l-ene-byl)phenyl)acrylic acid, E)-3-(4-((E)-2-(2-chloro-6-fluorenylphenyl)-1-(111-oxazol-5-yl)but-1-en-1-yl) Phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(7-a-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl) Phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(4-methyl-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl Phenyl)acrylic acid, (E)-3-(4-((Ε)-1-(7-methyl-1H-indazol-5-yl)-2-phenylbut-1-ene-1- (phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(6-fluorenyl-1H-indazol-5-yl)-2-phenylbut-1-ene-1 -yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(3-methyl-1H-indazol-5-yl)-2-phenylbut-1-ene- 1-yl)phenyl)acrylic acid, (E)-3-(4-((Ε)-1-(3_ chloro-1H-® pyrin-5-yl)-2-phenylbutan-1-ylide- 1-yl)benzyl)acrylic acid, (Ε)-3-(4·((Ε)-2-(4-Ga-2-methylphenyl)-1-(1Η-indazol-5-yl) But-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-(( Ε)-1-(1Η-oxazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-1 -(1H-carbazol-5-yl)-2-phenylpent-1-en-1-yl)phenyl)propene 158421.doc -6- 201216961 acid, (E)-3-(4-(( E)-2-(3-cyanophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4- ((E)-2-(4-cyanophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-( 4-((E)-4-Hydroxycarbazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl) Acrylic acid, (Ε)-3-(4·((Ε) -1-(1Η-indazol-5-yl)-4-decyloxy-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-(( Ζ)-1-(1Η-oxazol-5-yl)-3-decyloxy-2-phenylprop-1-en-1-yl)phenyl)acrylic acid, (E)· 3-(4- ((Ε)-1-(4-fluoro-1H.oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4- ((Ε)-1-(6-Gas-1H-carbazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4- ((Ε)-1-(1Η-carbazole-5-yl)-4-methyl-2-phenylpent-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4 -((E)-l-(4-Ga-1H-indazole-5 -yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-cyclopentyl-1-(1H-carbazole) -5-yl)·2·phenylvinyl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-cyclohexyl-1·(1Η-. Bora-5-yl)-2_phenylvinyl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(1 Η-0引0坐-5-yl)- 3-(methyl-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-3-cyclopropyl-1-(1H-吲) (E)-3-(4-((E)-2-(2-chlorophenyl)) 2 oxazol-5-yl)-2-phenylpropen-1-enyl)phenyl)acrylic acid -cyclopropylcarbazol-5-yl)vinyl)phenyl)acrylic acid, (E)-3-(4-((E)-l-(6-fluoro-1 Η- °引°圭-5 - (2-phenyl-butan-1-yl-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2 -Phenylhex-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-3·cyclopentyl-1-(1H-carbazole-5-yl)-2-benzene (E)-3-(4-((e)-2-(2-)-4-phenylene-1-(4-) ^-1Η-β 唾 -5-5-yl)but-1-en-1-yl)benzene 158421.doc 201216961 base) acrylic acid, (E)-3-(4_((E)-1-(7-fluoro) -1H-carbazol-5-yl)-2-propenylbut-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(2-chloro) ·4·Fluorophenyl)-1-(1Η-indazol-5-yl)-4-mercapto-1-en-1-yl)phenyl)propionic acid, (E)-3-(4 -((Z)-3 , 3-difluorooxazol-5-yl)-2-phenylprop-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(2) - gas-4-fluorophenyl)-1-(7-fluoro-1H-called 丨. sit-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-( 4-((E)-4-fluorooxazol-5-yl)-2-phenylbutan-1-phenyl)phenyl)acrylic acid, (E)-3-(4-((E)-4- Gas-2-(2-Ga-4-fluorophenyl)_ 1-(1Η-β丨β°-5-yl)but-1-en-1-yl)phenyl)propionic acid, (e )-3-(4_((Z)-3,3,3-trifluoro-1-(1H-D9 ° sit-5-yl)-2-phenylpropan-1-lean-i)) Acrylic acid, (Ε)-3·(4-((Ε)-1-(4-fluoro-1H-indazol-5-yl)-2-(4-IL-2-methylphenyl)butyl- 1-di-1-yl)phenyl)acrylic acid, (e)-3-(4-((E)-2-(4-carbo-2-ylphenyl)-1-(4-)- 1H-® 丨0 sit-5-yl) butyl-1_ene-1-yl)phenyl)acrylic acid, (E)-3_(4-((E)-2_cyclopropyl-1-(4) -fluoro_ιΗ_ carbazol-5-yl)-2-(4-fluoro-2-methylphenyl)vinyl)phenyl)acrylic acid, (E)-3-(4-((E)-2- (4-Chloro-2-methylphenyl)-2-cyclopropyl-1-(4-fluoro-ex-oxazol-5-yl)vinyl)phenyl)acrylic acid, (Ε)-3-( 4-((Ε)-1-(4-Gas-1H-carbazole-5·yl)- 2-(2-Ga-4-fluorophenyl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((Z)-2-(2-)-4 -fluorophenyl)-3,3·difluoro-1-(ih-indazol-5-yl)prop-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-( (E)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)-2-phenylvinyl)phenyl)acrylic acid, (E)-3-(4-(( E)-4-chloro-1-(4-fluoro-1H-carbazole·5-yl)-2·phenylbut-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-( 4-((Ε)-4-Gas-2-(2-Ga-4-fluorophenyl)-1-(4-fluoro-1H-indazol-5-yl)but-1-en-1-yl Phenyl)propene 158421.doc S 201216961 acid, (E)-3-(4-((E)-4-Ga-2-(4-fluorophenyl)-1-(1 Η- ° bow 丨-5-yl) But-1-en-1-yl)phenyl)propionic acid, (Ε)-3-(4-((Ε)-4-气-1-(4-敦_ 1H-吲(oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((Ε)-1-(1Η-carbazole-5-) ))-5-decyloxy-2-phenylindol-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(1Η-吲撒- 5-yl)-6-methoxy-2-phenylhex-1-en-1-yl)phenyl)acrylic acid, (E)-3-(.4-((E)-2_(2-gas -4-fluorophenyl)-1-(1Η-indazol-5-yl)-3-methyl -1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(3-(trifluoromethyl) Oxy)phenyl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2·cyclobutyl-1-(1Η-carbazole-5) -yl)-2-phenylvinyl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-(2- gas-4-fluorophenyl)-2_cyclobutyl- 1-(1Η-oxazol-5-yl)vinyl)phenyl)acrylic acid, (Ε)-3·(4-((Ε)-1-(3-fluoro-1Η-carbazol-5-yl)) -2-phenylbut-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-cyclobutyl-1-(3-fluoro-1Η-吲) Zyrid-5-yl)-2-phenylvinyl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2·(2- gas-4-fluorophenyl)-1-( 3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(2-)-4 -fluorophenyl)-2-cyclobutyl-1-(3-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylic acid, (E)-3-(4-((E)- Ethyl 2-(4-fluorophenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate, (Ε)-3-(4_((Ε -1_(1Η-oxazol-5-yl)-2-(2-decyloxyphenyl)but-1-en-1-yl)phenyl)acrylic acid ethyl ester, (Ε)-3-(4 -(( Ε)-1-(1Η-oxazol-5-yl)-2-(4-decyloxyphenyl)but-1-ene-byl)phenyl)acrylic acid ethyl ester, (E)-3-( 4-((E)-2-(3-hydroxyphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3- (4-((E)-2-(2-Phenylphenyl)-1-(1Η-α5|. Sodium-5-yl)but-1-en-1-yl)benzene 158421.doc -9- 201216961 base) acrylic acid, (E)-3-(4-((E)-2-(4-hydroxyphenyl) )-1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(3-butoxy) Phenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(4) -butoxyphenyl)-1-(1Η·oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1 -(1Η-carbazol-5-yl)-2·(2-(indolylsulfonyl)phenyl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4 -((Ε)-1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-methylacrylic acid, (Ε)-3-( 4-((Ζ)-1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)-3-methylphenyl)acrylic acid, (Ε)-3- (4-((Ε)-1-(1Η-indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-mercaptophenyl)acrylic acid, (E)-3 -(4-((Ζ)-1-(1Η-indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-ylphenyl) Acrylic acid, (Ζ)-3 -(4-((Ε)-1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-fluoroacrylic acid, (Ζ)-3 -(4-((Ε)-1 -(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)-2-ylacrylic acid, (Ε)-3-(4-((Ζ)-1 -(1 Η-carbazol-5-yl)-2-phenylbut-1-en-1-yl)-3-fluorophenyl)acrylic acid, (Ε)-3-(4-((Ζ)- 1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)-2-fluorophenyl)acrylic acid, (Ε)-3·(4-((Ζ)- 1-(1Η-oxazol-5-yl)-2-phenylbut-1-en-1-yl)-2-(trifluoromethyl)phenyl)acrylic acid, (E)-3-(4- ((Z)-1-(1H-carbazol-5-yl)-2-phenylbut-1-en-1-yl)-3-methoxyphenyl)acrylic acid, (Ε)-3-( 4-((Ζ)-1-(1Η-indazol-5-yl)-2-phenylbut-1-en-1-yl)-2-methoxyphenyl)acrylic acid, (E)-3 -(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1Η-. oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid Ethyl ester hydrochloride, (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1Η·oxazol-5-yl)but-1-ene -1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-(2,4-dichlorobenzene-10·158421.doc S 201216961)-1-(1Η-吲Ethyl-5-yl)but-1-en-1-yl)phenyl)acrylate, (E)-3-(4-((E)-2-(2,4-dichlorophenyl)- 1-(1Η-carbazole- 5-yl)but-1-ene-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2_(4-chloro-2-(trifluoromethyl)phenyl) -1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(2-)-4 -fluorophenyl)-2.cyclopropyl-1·(1Η-carbazol-5-yl)vinyl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-(4) -fluoro-2-(trifluoromethyl)phenyl)-1-(1H-indazol-5-yl)but-1-ene-1.yl)phenyl)acrylic acid, (E)-3-(4 -(l-(4-fluoro-1H-indazol-5-yl)-2-(4-fluoro-2-(trifluoromethyl)phenyl)butyl)phenyl)acrylic acid, (E)-3 -(4-((E)-2-(2,4-diphenyl)(4-fluoro-1indole-indol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, ( Ε)-3-(4-((Ε)-2-(4_Gas-2-(trifluoromethyl)phenyl)-1-(4-fluoro-1Η-carbazole-5(yl))- 1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-(2-chloro-4·))-1-yl-1-(1Η- °丨丨0 sit-5-yl)but-1-en-1-yl)benzine) acridine, (Ε)-3-(4-((Ε)-2-(2-chloro-4- Methoxyphenyl)-1-(1Η-carbazole-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2-( 2,4-diphenyl)-4-fluoro- 1-(4-Fluoro-1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-2·cyclopropyl) -2-(2,4-dichlorophenyl)-1-(4-fluoro-lH-indazol-5-yl)vinyl)phenyl)acrylic acid, (E)-3-(4-((E) )-2-(2-chloro-4-fluorophenyl)-2-cyclopropyl-1-(4-fluoro-1H-indazol-5-yl)vinyl)phenyl)acrylic acid, (E)- 3-(4-((E)-2-cyclopropyl-2-(2,4-dichlorophenyl)(1H-indazole-5())vinyl)phenyl)acrylic acid, (Ε)- 3-(4-((Ε)·2-(4-Ga-2-methylphenyl)_2_cyclopropyl-1·(1Η-indazol-5-yl)vinyl)phenyl)acrylic acid, (Ε)-3-(4-((Ε)-1-(1Η-indazol-5-yl)-2-(2-methyl-5-(methylsulfonyl)phenyl)butene-1- Alken-1-yl)phenyl)acrylic acid, (E)-3-(4- 158421.doc • 11 · 201216961 ((E)-l-(lH-carbazol-5-yl)-2-(4-曱oxy-2-methylphenyl)but-1-ene-1-yl)phenyl)acrylic acid, (E)_3_(4_((e)_2_(2_fluoro-4_methoxyphenyl)) -1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (e)-3-(4-((E)-2-(2-)-5 -Methoxyphenyl)-1-(1Η-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3_(4-((e)-2-(2-fluoro-4-(indolylsulfonyl)phenyl)-1-(1H-indazol-5-yl)but-1-ene -1-yl)phenyl)acrylic acid, jin)-3-(4-((£)-2-(2,4-diphenyl)-3,3,4,4,4-penta-1 -(111-吲0圭-5-yl)but-1·ene_ι_yl)phenyl)acrylic acid, (e)_3-(4-((E)-1-(1H-〇引°° _5_yl)-2-(3-(methylsulfonyl)phenyl)but-1-en-1-yl)phenyl)propionic acid, (E)-3-(4-(( E)-2-(2,4-diphenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (幻_ 3_(4_((幻_2_(2_气_ 3-methoxyphenyl)-1-(1Η-&quot; bow 丨. Sitting on -5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2-(2- gas_4_fluorophenyl)-3, 3,4,4,4-penta-1-(1H-indazol-5-yl)but-1-ene-1·yl)phenyl)acrylic acid, (e)_3_(4_((E)-2) -(4-chloro-2-cyanophenyl)-1_(ih-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-( (E)-2-(2-cyano-4-fluorophenyloxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (Ε)-3_(4·((ε ) 2-(2-cyano-4-(trifluoromethyl)phenyl)_ι_(ιη-carbazol-5-yl)butan-1·ene-ι_yl)phenyl)acrylic acid, (Ε)-3- (4-((Ε)-2-(2-Ga-4-cyanophenyl)_i_(1H-indolyl-5-yl)butyl-l-ene-i-yl)phenyl)acrylic acid, (e )_3-(4-((Ε)-2·(3-cyano-2-methylphenylindole-5-yl)butan-1-indole-i)yl)phenyl)acrylic acid, (E)- 3-(4-((E)-2-(4-cyano-2-methylphenyl)-1-(1H-indazol-5-yl)but-1-enyl)phenyl)acrylic acid , (e)_3_(4_((E)-2-(5-Cyano-2-methylphenyl)_i_(ih-carbazol-5-yl)but-1-small 158421.doc •12· 201216961 phenyl)acrylic acid, (E)-3-(4-((E)-2-(2-cyano-4-methoxyphenyl) -1-(1Η-oxazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)_3-(4-((E)-2-(2-chlorophenyl)) 1-(1-methyl-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, (E)-3-(4-((E)-2- ring) Butyl-1-(1-methyl-1H-° 弓b-5-yl)-2-phenylvinyl)phenyl)acrylic acid, (Ε)_3-(4·((Ε)-2- (2-Chloro-4-fluorophenyl)-1-(1-indolyl-1Η-indazol-5yl)buty-buten-1-yl)phenyl)acrylic acid, (E)-3-( 4-((E)-2-(2-Ga-4·fluorophenyl)-1-(1-(difluoromethyl)-1Η-indazol-5-yl)but-1-ene-1- Phenyl)acrylic acid, or a pharmaceutically acceptable salt thereof, or an N-oxide. A compound according to any one of claims 1, 2, 5, 6, 8 or 9, or a pharmaceutically acceptable salt thereof, or an N-oxide, for use in medicine. A compound according to any one of claims 2, 5, 6, 8 or 9, or a pharmaceutically acceptable salt thereof, or an N-oxide, for use in the treatment of cancer in a mammal. 12. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, or an N-oxide, for use in the treatment of a cancer suitable for use in a mammal treated with an estrogen receptor modulator. 13. A compound according to claim 、, or a pharmaceutically acceptable salt thereof, or a small oxygen compound for use in the treatment of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, or uterine cancer in a mammal. 14. The compound of any one of claim 1, 2, 5 '6, 8 or 9 or a pharmaceutically acceptable salt thereof, or N-oxide, for use in the treatment of cancer in a mammal, colon Rectal cancer, endometrial cancer, prostate cancer, India, uterine cancer, cervical cancer, lung cancer, leiomyoma, uterine smoothing 158421.doc •13- 201216961 Myoma, alcoholism, migraine, aortic aneurysm, myocardial infarction Susceptibility, aortic valve sclerosis, cardiovascular disease, coronary artery disease, hypertension, deep vein thrombosis, Graves' Disease, arthritis, multiple sclerosis, cirrhosis, hepatitis B, chronic liver disease, Bone mineral density, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis, Alzheimer's disease, Parkinson's disease, migraine, dizziness , anorexia nervosa, attention deficit hyperactivity disorder (ADHD), dementia, major depression, psychosis, age at menstruation, endometriosis, or infertility. I5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or an oxide. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, subcutaneous injection, oral administration, or topical administration. A pharmaceutical composition according to the above-mentioned item 15, wherein the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, (4), a dispersion, a solution, an emulsion, an ointment, or a lotion. 158421.doc 201216961 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 158421.doc